Piperazinyl-propyl-pyrazole derivatives as dopamine D4 receptor antagonists, and pharmaceutical compositions containing the same

ABSTRACT

The present invention relates to a novel piperazinyl-propyl-pyrazole derivative, a method of its preparation and a pharmaceutically acceptable composition comprising the same. The novel piperazinyl-propyl-pyrazole derivative of the present invention has superior selective affinity for dopamine D 4  receptor, can effectively inhibit psychotic behavior (cage climbing) induced by apomorphine, and has relatively low adverse effects in mouse rotarod test. Therefore, it can be developed as a therapeutic agent for the treatment and prevention of central nervous system (CNS) disorders, in particular, schizophrenia, attention deficit hyperactivity disorder, depression, stress diseases, panic disorder, phobia, obsessive-compulsive disorder, posttraumatic stress disorder, cognitive disorder, Alzheimer&#39;s disease, Parkinson&#39;s disease, anxiety, paraphrenia, mania, seizure disorder, personality disorder, migraine, drug addiction, alcohol addiction, obesity, eating disorder, and sleeping disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation Application of U.S. patentapplication Ser. No. 12/530,312, filed Sep. 8, 2009, which is a NationalStage Entry of PCT/KR2007/003415 filed Jul. 13, 2007, and claimspriority to Korean patent application number 10-2007-0022845, filed onMar. 8, 2007, which is incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to a piperazinyl-propyl-pyrazolederivative, a method of its preparation and a pharmaceuticallyacceptable salt comprising the same.

BACKGROUND ART

Dopamine is a neurotransmitter essential for neuronal signaltransduction in animal brains including humans. Dopamine receptorantagonists inhibiting the binding between dopamine and its cognatereceptors have been used as a therapeutic agent for treating centralnervous system (CNS) disorders such as schizophrenia. Since thediscovery of psychotropic effect chloropromazine in 1952, numerouspsychotropic drugs with various chemical structures have been developed.Drugs such as chloropromazine and haloperidol, which typically work ondopamine D₂ receptors, are shown to have generally good therapeuticprofiles for the treatment of schizophrenia. However, their clinicalapplications are greatly restricted because they are known to causeextrapyramidal side effects (EPS) in addition to other adverse effectssuch as sexual dysfunction, orthostatic hypotension, excessive sedationand gain in body weight, thus preventing patients from managing a normallife. Further, these drugs are shown to improve the symptoms ofschizophrenia such as delusion or hallucination but were unable toimprove apathy, atrophy and impairment of cognitive function at all[Wong, A. H. C. et al., Expert. Opin. Ther. Targets 1999, 3, 571-586;Chatterjee, A. et al., Am. J. Psychiat. 1995, 152, 1724-1729].Therefore, there has been a longfelt need for the development of a newversion of drug that can remedy the above-mentioned drawbacks of thetypical therapeutic drugs for the treatment of mental disorders. As aresult, atypical psychotropic drugs such as clozapine, olanzapine,risperidone, quetiapine and aripiprazole have been developed recently tomeet the above requirement. Among them, the most representative D₄antagonist is clozapine. Clozapine has shown a relatively low affinityfor dopamine D₂ receptor but a relatively high selectivity for dopamineD₄ receptor. It also manifested a high affinity for serotonin (5-HT)receptor such as 5-HT₆ in several reports (Van Tol, H. H. M et al.,Nature 1991, 350, 610-614; Oak, J. N. et al., Eur. J. Pharmacol. 2000,405, 303-327). Clozapine is known to have relatively reduced sideeffects compared with those of typical drugs acting on dopamine D₂receptors. However, it still has extrapyramidal side effects (EPS) andshows no efficacy in about 30-50% of patients. Based on these findings,intensive researches have been recently performed to develop thedopamine D₄ receptor antagonists with an improved selectivity for the D₄receptor or the antagonists showing a moderate affinity for serotonin5-HT₂ receptor in addition (Lober, S. et al., Bioorg. Med. Chem. Lett.2006, 16, 2955-9; Bartolome, J. M. et al., Bioorg. Med. Chem. Lett.2005, 15, 2898-901; Arora, J. et al., Bioorg. Med. Chem. Lett. 2005, 15,5253-5256; Nakane, M. et al., Neuropharmacology 2005, 49, 112-121).Meanwhile, dopamine receptors have been reported to be closelyassociated with schizophrenia, Parkinson's disease, attention deficithyperactivity disorder (ADHD), depression, dementia, migraine,aggressive and suicidal behaviors (Todd, R. D. & O'Malley, K. L., TIPS2001, 55-56; Roth, B. L. et al., Psychopharmacology 2004, 174, 17-24).

The inventors of the present invention synthesized novelpiperazinyl-propyl-pyrazole compounds having high affinity for thedopamine D₄ receptor and completed the present invention by confirmingthat these compounds indeed have high affinity for the dopaminereceptor.

Therefore, in an embodiment, the present invention provides novelpiperazinyl-propyl-pyrazole derivatives with a novel structureintroduced with various substituents, and its pharmaceuticallyacceptable salt.

In another embodiment, the present invention provides a novelpiperazinyl-propyl-pyrazole derivative and a method of its preparation.

In a further embodiment, the present invention provides a pharmaceuticalcomposition comprising a novel piperazinyl-propyl-pyrazole derivative asan active ingredient effective in the prevention and treatment of CNSdisorders.

DISCLOSURE OF INVENTION

The present invention relates to piperazinyl-propyl-pyrazole derivativesrepresented by the following formula 1 having selective antagonisticactivity on dopamine D₄ receptor and its pharmaceutically acceptablesalts thereof:

wherein R¹ is a C₁-C₁₀ alkyl group, or a substituted or unsubstitutedaryl or heteroaryl group; one of R² and R³ is a hydrogen atom, while theother is a C₁-C₁₀ alkyl group, benzyl group, or substituted orunsubstituted aryl or heteroaryl group; R⁴, R⁵, R⁶ and R⁷, being same ordifferent with one another, are independently a hydrogen atom or aC₁-C₁₀ alkyl group; R⁸, R⁹, R¹⁰, R¹¹ and R¹², being same or differentwith one another, are independently a hydrogen atom, a halogen atom, aC₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a bis(substituted orunsubstituted aryl)alkylene group, a benzyl group, a nitro group, ahydroxyl group, a cyano group, an amino group, a mono or dialkylaminogroup, an alkylcarbonylamino group, an aminosulfonyl group, a mono ordialkylaminosulfonyl group, an alkylcarbonyl group, or analkyloxycarbonyl group; the dotted line represents a single or doublebond which depends on the substitution of R² and R³ but maintains thearomaticity of a pyrazole ring; the aryl group represents a phenylgroup, said heteroaryl group represents a thiophenyl group or a pyridylgroup, and said substituted aryl or heteroaryl group represents an arylor a heteroaryl group with from 1 to 3 substituents selected from thegroup consisting of a halogen atom, a nitro group, a C₁-C₁₀ alkyl group,a C₁-C₁₀ alkoxy group, a C₁-C₁₀ haloalkyl group, and a C₁-C₁₀haloalkoxy.

The substituents of the compounds of the present invention are furtherdefined as set forth hereunder.

As used herein, “alkyl” refers to a C₁-C₁₀ straight, branched or cyclicaliphatic saturated or unsaturated hydrocarbon group, preferably C₁-C₆straight, branched or cyclic aliphatic saturated or unsaturatedhydrocarbon group. More specifically, it may refer to methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl,neo-pentyl, cyclopentyl, cyclobutylmethyl, n-hexyl, isohexyl,cyclohexyl, benzyl, phenylethyl and the like.

As used herein, “alkoxy” refers to a hydroxyl group wherein a hydrogenatom is substituted by the above-defined “alkyl”. More specifically, itmay refer to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,tert-butoxy, benzyloxy, phenylethoxy and the like.

As used herein, “aryl” practically refers to all the aromatic rings.Aryl herein refers to a single aromatic ring comprising at least 5 fivecarbon atoms, preferably 5-20 carbon atoms, or an aromatic ringincluding 1-5 heteroatoms selected from a nitrogen, an oxygen or asulfur atom, preferably 1-3 heteroatoms additionally. It also refers tothe structure with a few adjoining rings that is resonance-stabilized.More specific examples are phenyl, naphthyl, pyridyl, pirazine,pyrimidine, pyridazine, triazine, imidazole, triazole, quinoline,isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole,isooxazole, thiazole, isothiazole, thiadiazole, oxadiazole, pyrrole,furan, thiophene and the like.

Further, aryl may have at least one substituent selected from the groupconsisting of alkyl, halogen, alkoxy, phenoxy, nitro, hydroxy, cyano,amino, mono or dialkylamino, alkylcarbonylamino, aminosulfonyl, mono ordialkylaminosulfonyl, alkylcarbonyl, alkyloxycarbonyl.

Piperazinyl-propyl-pyrazole derivatives are represented by the aboveformula 1 of the present invention, wherein, preferably, R¹ is a C₁-C₁₀alkyl group, a substituted or unsubstituted phenyl group, or asubstituted or unsubstituted thiophenyl group; one of R² and R³ is ahydrogen atom, while the other is a C₁-C₁₀ alkyl group, benzyl group, asubstituted or unsubstituted phenyl group, or a substituted orunsubstituted pyridyl group; R⁴, R⁵, R⁶ and R⁷, being same or differentwith one another, are independently a hydrogen atom or a C₁-C₁₀ alkylgroup; R⁸, R⁹, R¹⁰, R¹¹ and R¹², being same or different with oneanother, are independently a hydrogen atom, a halogen atom, a C₁-C₁₀alkyl group, a C₁-C₁₀ alkoxy group, bis(substituted or unsubstitutedphenyl)alkylene group, or a benzyl group; the dotted line represents asingle bond or a double bond which depends on the substitution of R² andR³ but maintains the aromaticity of a pyrazole ring; the substitutedphenyl group, thiophenyl group or pyridyl group are independently aphenyl group, a thiophenyl group or a pyridyl group with from 1 to 3substituents selected from the group consisting of a halogen atom, anitro group, a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a C₁-C₁₀haloalkyl group, and a C₁-C₁₀ haloalkoxy group.

In the piperazinyl-propyl-pyrazole derivatives represented by the aboveformula 1 of the present invention, preferably, R¹ is a phenyl,4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,2-thiophenyl, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; oneof R² and R³ is a hydrogen atom, while the other is t-butyl, benzyl,phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chlorophenyl, 4-fluorophenyl,4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,4-trifluoromethoxyphenyl, or 2-pyridyl; R⁴, R⁵, R⁶ and R⁷, being same ordifferent with one another, are independently a hydrogen atom or amethyl group; R⁸, R⁹, R¹⁰, R¹¹ and R¹², being same or different with oneanother, are independently a hydrogen atom, a chloro, fluoro, methyl,methoxy, or bis(4-fluorophenyl)methylene.

In particular, piperazinyl-propyl-pyrazole derivatives represented bythe above formula 1 are preferably as follows:

-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 1)-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 2);-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 3);-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 4);-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 5);-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 6);-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 7);-   4-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 8);-   1-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 9);-   1-(3-(1-tert-butyl-3-phenyl-1H-pyrazol-5-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 10);-   1-phenyl-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 11);-   1-(2-fluorophenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 12);-   1-(4-chlorophenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 13);-   1-(2,4-dimethylphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 14);-   1-(3,4-dimethylphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 15);-   1-(2,3-dimethylphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 16);-   1-(4-methoxyphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 17);-   2-methyl-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine    (Compound 18);-   1-(3,4-dichlorophenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 19);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 20);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 21);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 22);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 23);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 24);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 25);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 26);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 27);-   4-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 28);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 29);-   1-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 30);-   1-phenyl-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 31);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 32);-   1-(4-chlorophenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 33);-   1-(2,4-dimethylphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 34);-   1-(3,4-dimethylphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 35);-   1-(2,3-dimethylphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 36);-   1-(4-methoxyphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 37);-   2-methyl-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine    (Compound 38);-   1-(3,4-dichlorophenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 39);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 40);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 41);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 42);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 43);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 44);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 45);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 46);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 47);-   4-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 48);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 49);-   1-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 50);-   1-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 51);-   1-(2-fluorophenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 52);-   1-(4-chlorophenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 53);-   1-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 54);-   1-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 55);-   1-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 56);-   1-(4-methoxyphenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 57);-   4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 58);-   1-(3,4-dichlorophenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 59);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 60);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 61);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 62);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 63);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 64);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 65);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 66);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 67);-   4-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 68);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 69);-   1-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 70);-   1-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 71);-   1-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 72);-   1-(4-chlorophenyl)-4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 73);-   1-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 74);-   1-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 75);-   1-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 76);-   1-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 77);-   4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 78);-   1-(3,4-dichlorophenyl)-4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 79);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 80);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 81);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 82);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 83);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 84);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 85);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 86);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 87);-   4-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 88);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 89);-   1-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 90);-   1-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 91);-   1-(2-fluorophenyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 92);-   1-(4-chlorophenyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 93);-   1-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 94);-   1-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 95);-   1-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 96);-   1-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 97);-   4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 98);-   1-(3,4-dichlorophenyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 99);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 100);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 101);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 102);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 103);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 104);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 105);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 106);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 107);-   4-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 108);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 109);-   1-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 110);-   1-phenyl-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 111);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 112);-   1-(4-chlorophenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 113);-   1-(2,4-dimethylphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 114);-   1-(3,4-dimethylphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 115);-   1-(2,3-dimethylphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 116);-   1-(4-methoxyphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 117);-   2-methyl-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine    (Compound 118);-   1-(3,4-dichlorophenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 119);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine    (Compound 120);-   1-phenyl-4-(3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 121);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 122);-   1-phenyl-4-(3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 123);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 124);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine    (Compound 125);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 126);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 127);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 128);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 129);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 130);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 131);-   4-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 132);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 133);-   1-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 134);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-phenylpiperazine    (Compound 135);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(2-fluorophenyl)piperazine    (Compound 136);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(4-chlorophenyl)piperazine    (Compound 137);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(2,4-dimethylphenyl)piperazine    (Compound 138);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(3,4-dimethylphenyl)piperazine    (Compound 139);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(2,3-dimethylphenyl)piperazine    (Compound 140);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(4-methoxyphenyl)piperazine    (Compound 141);-   4-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-2-methyl-1-m-tolylpiperazine    (Compound 142);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(3,4-dichlorophenyl)piperazine    (Compound 143);-   1-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine    (Compound 144);-   1-phenyl-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 145);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 146);-   1-(4-chlorophenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 147);-   1-(2,4-dimethylphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 148);-   1-(3,4-dimethylphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 149);-   1-(2,3-dimethylphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 150);-   1-(4-methoxyphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 151);-   2-methyl-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine    (Compound 152);-   1-(3,4-dichlorophenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 153);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine    (Compound 154);-   1-phenyl-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 155);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 156);-   1-(4-chlorophenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 157);-   1-(2,4-dimethylphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 158);-   1-(3,4-dimethylphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 159);-   1-(2,3-dimethylphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 160);-   1-(4-methoxyphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 161);-   2-methyl-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)-1-m-tolylpiperazine    (Compound 162);-   1-(3,4-dichlorophenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 163);-   1-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 164);-   1-(2-fluorophenyl)-4-(3-(1-(3-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 165)-   1-(2-fluorophenyl)-4-(3-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 166)-   1-(2-fluorophenyl)-4-(3-(1-(4-methylphenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 167)-   1-(2-fluorophenyl)-4-(3-(1-(4-fluorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 168)-   1-(2-fluorophenyl)-4-(3-(1-(4-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 169)-   1-(2-fluorophenyl)-4-(3-(1-(4-trifluorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 170)-   1-(2-fluorophenyl)-4-(3-(1-(4-trifluoromethoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 171)-   1-(2-fluorophenyl)-4-(3-(1-(4-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 172)-   1-(2-fluorophenyl)-4-(3-(1-benzyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 173)-   1-(2-fluorophenyl)-4-(3-(1-(3-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 174)-   1-(2-fluorophenyl)-4-(3-(1-(2′-pyridyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 175)-   1-phenyl-4-(3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 176);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 177);-   1-phenyl-4-(3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 178);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 179);-   1-(2-fluorophenyl)-4-(3-(1-(3-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 180)-   1-(2-fluorophenyl)-4-(3-(1-(4-methoxyphenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 181)-   1-(2-fluorophenyl)-4-(3-(1-(4-methylphenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 182)-   1-(2-fluorophenyl)-4-(3-(1-(4-fluorophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 183)-   1-(2-fluorophenyl)-4-(3-(1-(4-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 184)-   1-(2-fluorophenyl)-4-(3-(1-(4-trifluoromethylphenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 185)-   1-(2-fluorophenyl)-4-(3-(1-(4-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 186)-   1-(2-fluorophenyl)-4-(3-(1-benzyl-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 187)-   1-(2-fluorophenyl)-4-(3-(1-(3-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 188)-   1-(2-fluorophenyl)-4-(3-(1-(2′-pyridyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 189)-   1-phenyl-4-(3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 190);-   1-(2-fluorophenyl)-4-(3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propyl)piperazine    (Compound 191).

In an embodiment, the present invention provides a method for preparinga piperazinyl-propyl-pyrazole derivative represented by the aboveformula 1 by performing reductive amination between a pyrazole aldehydederivative represented by the following formula 2 and a piperazinederivative represented by the following formula 3:

wherein, in the above reaction scheme I, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹ and R¹² are same as defined above.

The reductive amination according to the above reaction scheme I isperformed as follows: first, pyrazole aldehyde derivative andpiperazine, both dissolved in a solvent, are stirred at room temperaturealong with a molecular sieve under nitrogen atmosphere, dropwisely addedwith a base, stirred again at room temperature for 0.5-1 hr and thenreduced by adding a reducing agent to form a piperazinyl-propyl-pyrazolederivative represented by the above formula 1.

The solvent used in the reductive amination according to the abovereaction scheme I is a conventional solvent, examples of which includemethylene chloride, chloroform, 1,2-dichloroethane and the like. In thepresent invention, methylene chloride was used.

The molecular sieve used in the present invention has a size of 0.1-100in diameter, preferably 0.1-10. In the present invention, a molecularsieve with a size of 4 in diameter was used.

The base used in the present invention includes alkylamines such astriethylamine, diisopropylethylamine and the like, or alkali metal oralkalic metal salt such as Na₂CO₃, K₂CO₃ and the like. In the presentinvention, diisopropylethylamine was used. The base is used 1-5equivalents per reactant, preferably 1 equivalent.

Examples of reducing agents are NaBH₄, NaBH(OAc)₃ and the like, andNaBH(OAc)₃ was used in the present invention. The reducing agent is used1-10 equivalents, preferably 3 equivalents.

Reaction is performed for about 1-24 hrs, preferably 12-15 hrs. Reactionis preferably performed at room temperature. Upon completion ofreaction, the resultant is added with water to eliminate any remainingreducing agent, and then separated via a conventional method such ascolumn chromatography to finally obtain pure piperazinyl-propyl-pyrazolederivatives.

In the above method according to reaction scheme I, the reactionintermediates of a pyrazole aldehyde derivative represented by the aboveformula 2 and a piperazine derivative represented by the above formula 3are known compounds and can be easily synthesized by using a knownmethod.

As for a pyrazole aldehyde derivative represented by the above formula 2can be synthesized by reacting β-keto ketones with hydrazine.

The method of synthesizing the pyrazole aldehyde derivative representedby the above formula 2 is shown in the following reaction scheme II.

In the above reaction scheme II, R¹, R², and R³ are independently sameas defined above.

As shown in the above reaction scheme II, a ketone compound representedby the above formula 4 and γ-butyrolactone are reacted at 30˜50° C. inthe presence of benzene as a solvent after adding NaOMe to produce adiketone compound represented by the above formula 5. The diketonecompound represented by the above formula 5 is reacted with hydrazine toproduce a pyrazole alcohol derivative represented by the above formula6a or 6b. Here, if R¹ is an aryl group a pyrazole alcohol derivativerepresented by the above formula 6a is obtained, while pyrazole alcoholderivatives represented by both the above formula 6a and 6b are obtainedif R¹ is an alkyl group.

Each of the pyrazole alcohol derivatives represented by the aboveformula 6a or 6b is oxidized by using an oxidizing agent such as PCC(pyridium chlorochromate) to obtain a pyrazole aldehyde derivativerepresented by the above formula 2a or 2b. The detailed syntheticmethods are described in the following examples.

The compound represented by the above formula 1 of the present inventionhas a superior selective affinity for dopamine D₄ receptor, caneffectively inhibit the psychotic behavior (cage climbing) of miceinduced by apomorphine, and exhibited relatively low adverse effects inmouse rotarod test. Therefore, it has potential to be developed as atherapeutic agent for the treatment and prevention of CNS disorders, inparticular, schizophrenia, attention deficit hyperactivity disorder,depression, stress diseases, panic disorder, phobia,obsessive-compulsive disorder, posttraumatic stress disorder, cognitivedisorder, Alzheimer's disease, Parkinson's disease, anxiety,paraphrenia, mania, seizure disorder, personality disorder, migraine,drug addiction, alcohol addiction, obesity, eating disorder, andsleeping disorder.

Therefore, the pharmaceutical composition of the present inventioncomprises a compound represented by the above formula 1 or itspharmaceutically acceptable salts thereof as active ingredients and thusincludes a pharmaceutical composition effective in the treatment andprevention of CNS disorders.

The pharmaceutically acceptable salts of the present invention are thosewhich can be manufactured by using a method known in the art, forexample, salts with inorganic acids such as hydrochloric acid, bromicacid, sulfuric acid, sodium hydrogen sulfate, phosphate, nitrate,carbonate and the like; and salts with organic acids such as formicacid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoicacid, citric acid, maleic acid, malonic acid, tartaric acid, gluconicacid, lactic acid, gestisic acid, fumaric acid, lactobionic acid,salicylic acid, trifluoroacetic acid and acetylsalicylic acid (aspirin);or salts with amino acids such as glycine, alanine, valine, isoleucine,serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine,tyrosine, proline and the like; salts with sulfonic acid such as methanesulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate andthe like; metal salts by reaction with an alkali metal such as sodium,potassium and the like; or salts with ammonium ion and the like.

The pharmaceutical composition can be prepared in the form of, forexample, tablets, capsules, troches, liquids, suspensions, etc., fororal or intraperitoneal administration, by adding the compoundrepresented by the above formula 1 or its pharmaceutically acceptablesalts with a conventional non-toxic pharmaceutically acceptable additivesuch as a carrier, a reinforcing agent, an excipient, and the like, forthe prevention and treatment of various kinds of CNS disorders.

Examples of excipients to be used in the pharmaceutical composition ofthe present invention include a sweetener, a binder, a solubilizer, asolubilization builder, a wetting agent, an emulsifier, an isotonicagent, an adsorbent, a disintegrator, an antioxidant, a preservative, alubricant, a filler, a flavoring agent, etc. For example, lactose,dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc,stearate, stearin, magnesium stearate, magnesium aluminosilicate,starch, gelatin, tragacanth Gum, alginic acid, sodium alginate,methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol,polyethylene glycol, polyvinylpyrolidone, sodium hydroxide, potassiumhydroxide, orange essence, strawberry essence, vanilla flavor and thelike.

The amount of dosage of the compound represented by the formula 1 of thepresent invention can vary depending on the patient's age, body weight,sex, type of administration, health conditions, seriousness of diseaseand the like. In general, the dosage is 0.01-5,000 mg/day, and it can beadministered once or a few times daily at regular intervals afterconsulting with a physician.

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples are embodiments of the methods for preparingcompound represented by the above formula 1 according to the reactionscheme I, and they should not be construed as limiting the scope of thepresent invention.

EXAMPLE Example 11-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 1)

3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 312 mmol) and1-phenylpiperazine (0.047 mL, 0.312 mmol) were dissolved in 5 mL ofCH₂Cl₂, and then 0.7 g of 4 molecular sieve powder was added thereto andstirred. Diisopropylethylamine (DIPEA; 54 mL, 0.312 mmol) was slowlyadded thereto, and stirred for 30 min at room temperature. Then,NaBH(OAc)₃ (231 mg, 1.092 mmol) was added thereto and stirred for 12hours at room temperature. The reaction progress and completion wereconfirmed by TLC. Upon completion of the reaction, water (0.1 mL) wasadded to the reaction mixture and then stirred for 3 min. 81 mg (64%) oftarget compound was obtained via column chromatography(EtOAc:Hexane=4:1, v/v).

¹H NMR (400 MHz, MeOH-d₄) δ 7.62-7.51 (m, 5H), 7.41-7.34 (m, 2H),7.26-7.23 (m, 2H), 7.10 (t, 1H, J=7.3 Hz), 6.67 (s, 1H), 3.90-3.48 (m,8H), 3.43-3.38 (m, 2H), 3.06 (t, 2H, J=7.7 Hz), 2.41-2.39 (m, 2H), 1.61(s, 9H).

Example 21-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 2)

79 mg (55%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80mg, 0.312 mmol), 1-(2-fluorophenyl)piperazine (56 mg, 0.312 mmol), DIPEA(82 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.59-7.41 (m, 5H), 7.20-7.03 (m, 4H), 6.50(s, 1H), 3.84-3.69 (m, 2H), 33.69-3.54 (m, 2H), 3.43-3.13 (m, 6H),3.11-2.88 (m, 2H), 2.38-2.22 (m, 2H), 1.56 (s, 9H).

Example 31-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 3)

101 mg (68%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal(80 mg, 0.312 mmol), 1-(4-chlorophenyl)piperazine (84 mg, 0.312 mmol),DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.58-7.40 (m, 5H), 7.27 (d, 2H, J=8.5 Hz),7.01 (d, 2H, J=8.7 Hz), 6.44 (s, 1H), 3.97-3.62 (m, 4H), 3.42-3.08 (m,6H), 2.99-2.89 (m, 2H), 2.43-2.20 (m, 2H), 1.54 (s, 9H).

Example 41-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 4)

99 mg (68%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80mg, 0.312 mmol), 1-(2,4-dimethylphenyl)piperazine (59 mg, 0.312 mmol),DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.62-7.39 (m, 5H), 7.08-6.95 (m, 3H), 6.51(s, 1H), 3.79-3.53 (m, 2H), 3.42-3.11 (m, 8H), 3.02-2.90 (m, 2H),2.48-2.21 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 1.57 (s, 9H).

Example 51-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 5)

62 mg (71%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50mg, 0.195 mmol), 1-(3,4-dimethylphenyl)piperazine (35.4 mg, 0.186 mmol),DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)₃ (118 mg, 0.558 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.38 (m, 5H), 7.08 (d, 1H, J=8.1 Hz),6.93 (s, 1H), 6.85 (d, 1H, J=7.9 Hz), 6.39 (s, 1H), 3.73-3.40 (m, 8H),3.40-3.23 (m, 2H), 2.93-2.78 (m, 2H), 2.38-2.13 (m, 2H), 2.26 (s, 3H),2.20 (s, 3H), 1.53 (s, 9H).

Example 61-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 6)

39 mg (45%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50mg, 0.195 mmol), 1-(2,3-dimethylphenyl)piperazine (35.4 mg, 0.186 mmol),DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)₃ (118 mg, 0.558 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.32 (m, 5H), 7.13-6.89 (m, 3H), 6.15(s, 1H), 3.77-3.60 (m, 2H), 3.49-3.04 (m, 8H), 2.81 (t, 2H, J=7.3 Hz),2.31-2.12 (m, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.47 (s, 9H).

Example 71-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 7)

62 mg (71%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50mg, 0.195 mmol), 1-(4-methoxyphenyl)piperazine (49 mg, 0.186 mmol),DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)₃ (118 mg, 0.558 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (br s, 1H), 7.50-7.26 (m, 5H), 6.95(d, 2H, J=8.6 Hz), 6.85 (d, 2H, J=8.5 Hz), 6.02 (s, 1H), 3.68 (s, 3H),3.68-3.50 (m, 4H), 3.28-3.00 (m, 6H), 2.59 (t, 2H, J=7.1 Hz), 2.18-2.20(m, 2H), 1.35 (s, 9H)

Example 84-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 8)

64 mg (44%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80mg, 0.312 mmol), 2-methyl-1-m-tolylpiperazine (59 mg, 0.312 mmol), DIPEA(82 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.62-7.41 (m, 8H), 7.41-7.28 (m, 1H), 6.57(s, 1H), 4.48-4.32 (m, 1H), 4.21-4.06 (m, 1H), 4.06-3.74 (m, 4H),3.74-3.58 (m, 1H), 3.58-3.30 (m, 2H), 3.14-2.97 (m, 2H), 2.43 (s, 3H),2.41-2.24 (m, 2H), 1.59 (s, 9H), 1.21 (d, 3H, J=4.9 Hz)

Example 91-(3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 9)

74 mg (47%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80mg, 0.312 mmol), 1-(3,4-dichlorophenyl)piperazine (72 mg, 0.312 mmol),DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.58-7.34 (m, 6H), 7.22-7.17 (m, 1H),7.00-6.98 (m, 1H), 6.32 (s, 1H), 3.98-3.83 (m, 2H), 3.79-3.66 (m, 2H),3.99-3.00 (m, 6H), 2.88 (t, 2H, J=6.9 Hz), 2.32-2.18 (m, 2H), 1.51 (s,9H)

Example 101-(3-(1-tert-butyl-3-phenyl-1H-pyrazol-5-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 10)

111 mg (63%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal(80 mg, 0.312 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (90 mg,0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.76-7.57 (m, 4H), 7.51-7.33 (m, 5H), 7.12(t, 4H, J=8.4 Hz), 6.24 (s, 1H), 3.71-3.43 (m, 4H), 3.36-2.87 (m, 11H),2.82 (t, 2H, J=7.1 Hz), 2.24-2.09 (m, 2H), 1.48 (s, 9H)

Example 11 1-phenyl-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 11)

100 mg (94%) of target compound was obtained by using a method same asin Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (76 mg,0.275 mmol), 1-phenylpiperazine (0.038 mL, 0.250 mmol), DIPEA (44 mL,0.250 mmol) and NaBH(OAc)₃ (185 mg, 0.875 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.33-7.21 (m, 10H), 6.95 (d, 1H, J=8.1 Hz),6.87 (t, 2H, J=7.3 Hz), 6.37 (s, 1H), 3.34-3.19 (m, 4H), 2.83-2.69 (m,4H), 2.80 (t, 2H, J=7.6 Hz), 2.63 (t, 2H, J=7.5 Hz), 2.10-1.92 (m, 2H)

Example 121-(2-fluorophenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 12)

74 mg (83%) of target compound was obtained by using a method same as inExample 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg,0.199 mmol), 1-(2-fluorophenyl)piperazine (0.026 mL, 0.166 mmol), DIPEA(35 mL, 0.199 mmol) and NaBH(OAc)₃ (148 mg, 0.697 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.54-7.43 (m, 3H), 7.43-7.22 (m, 7H),7.14-6.99 (m, 4H), 6.79 (s, 1H), 3.82-3.63 (m, 2H), 3.63-3.50 (m, 2H),3.43-3.25 (m, 4H), 3.21-3.06 (m, 2H), 3.02-2.90 (m, 2H), 2.42-2.23 (m,2H)

Example 131-(4-chlorophenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 13)

106 mg (74%) of target compound was obtained by using a method same asin Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg,0.289 mmol), 1-(4-chlorophenyl)piperazine (78 mg, 0.289 mmol), DIPEA (76mL, 0.434 mmol) and NaBH(OAc)₃ (184 mg, 0.868 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.42 (m, 3H), 7.42-7.30 (m, 5H),7.30-7.22 (m, 4H), 7.00 (d, 2H, J=8.8 Hz), 6.75 (s, 1H), 3.91-3.62 (m,4H), 3.43-3.19 (m, 4H), 3.19-2.90 (m, 2H), 3.00 (t, 2H, J=6.5 Hz),2.40-2.22 (m, 2H)

Example 141-(2,4-dimethylphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 14)

91 mg (64%) of target compound was obtained by using a method same as inExample 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg,0.289 mmol), 1-(2,4-dimethylphenyl)piperazine (55 mg, 0.289 mmol), DIPEA(76 mL, 0.434 mmol) and NaBH(OAc)₃ (184 mg, 0.868 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.52-7.43 (m, 3H), 7.42-7.23 (m, 7H), 7.03(s, 1H), 7.00 (d, 1H, J=8.3 Hz), 6.94 (d, 1H, J=8.1 Hz), 6.74 (s, 1H),3.83-3.60 (m, 2H), 3.48-3.29 (m, 4H), 3.29-3.01 (m, 4H), 2.97 (t, 2H,J=6.1 Hz), 2.40-2.24 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H)

Example 151-(3,4-dimethylphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 15)

74 mg (83%) of target compound was obtained by using a method same as inExample 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg,0.199 mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.166 mmol), DIPEA(0.035 mL, 0.199 mmol) and NaBH(OAc)₃ (148 mg, 0.697 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.41-7.18 (m, 10H), 7.11 (d, 1H, J=8.4 Hz),6.87 (s, 1H), 6.79 (d, 1H, J=7.6 Hz), 6.58 (s, 1H), 3.97-3.50 (m, 4H),4.41-4.32 (m, 4H), 3.23-2.98 (m, 2H), 2.98-2.81 (m, 2H), 2.35-2.25 (m,2H), 2.24 (s, 3H), 2.19 (s, 3H)

Example 161-(2,3-dimethylphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 16)

77 mg (81%) of target compound was obtained by using a method same as inExample 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (64 mg,0.231 mmol), 1-(2,3-dimethylphenyl)piperazine (40 mg, 0.210 mmol), DIPEA(0.037 mL, 0.210 mmol) and NaBH(OAc)₃ (156 mg, 0.735 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.42 (m, 3H), 7.40-7.22 (m, 7H), 7.07(t, 1H, J=7.7 Hz), 7.00 (d, 1H, J=7.4 Hz), 6.87 (d, 1H, J=7.9 Hz), 6.60(s, 1H), 3.79-3.60 (m, 2H), 3.42-3.25 (m, 4H), 3.25-3.11 (m, 2H),3.09-2.98 (m, 2H), 2.95 (t, 2H, J=6.9 Hz), 2.36-2.20 (m, 2H), 2.26 (s,3H), 2.24 (s, 3H)

Example 171-(4-methoxyphenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 17)

64 mg (93%) of target compound was obtained by using a method same as inExample 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (46 mg,0.166 mmol), 1-(4-methoxyphenyl)piperazine (40 mg, 0.151 mmol), DIPEA(0.026 mL, 0.151 mmol) and NaBH(OAc)₃ (96 mg, 0.453 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.37 (m, 3H), 7.37-7.30 (m, 5H),7.30-7.21 (m, 2H), 7.19 (d, 2H, J=6.6 Hz), 6.94 (d, 2H, J=7.4 Hz), 6.63(s, 1H), 3.77 (s, 3H), 3.73-3.45 (m, 8H), 3.45-3.33 (m, 2H), 3.02-2.81(m, 2H), 2.40-2.20 (m, 2H)

Example 182-methyl-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine(Compound 18)

107 mg (66%) of target compound was obtained by using a method same asin Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (110 mg,0.398 mmol), 2-methyl-1-m-tolylpiperazine (69 mg, 0.362 mmol), DIPEA(0.063 mL, 0.362 mmol) and NaBH(OAc)₃ (269 mg, 1.267 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.57-7.12 (m, 14H), 6.64 (s, 1H), 4.40-4.20(m, 1H), 4.09-3.68 (m, 5H), 3.68-3.54 (m, 1H), 3.54-3.37 (m, 2H),3.06-2.83 (m, 2H), 2.49-2.19 (m, 2H), 2.41 (s, 3H), 1.26-1.03 (m, 3H)

Example 191-(3,4-dichlorophenyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 19)

110 mg (72%) of target compound was obtained by using a method same asin Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg,0.289 mmol), 1-(3,4-dichlorophenyl)piperazine (67 mg, 0.289 mmol), DIPEA(0.076 mL, 0.434 mmol) and NaBH(OAc)₃ (184 mg, 0.868 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.52-7.39 (m, 3H), 7.39-7.30 (m, 6H),7.30-7.22 (m, 2H), 7.14-7.08 (m, 1H), 6.98-6.87 (m, 1H), 6.72 (s, 1H),4.90-4.78 (m, 2H), 4.78-4.67 (m, 2H), 4.42-4.19 (m, 6H), 4.13-4.30 (m,2H), 2.96 (t, 2H, J=6.5 Hz), 2.38-2.21 (m, 2H)

Example 201-(bis(4-fluorophenyl)methyl)-4-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 20)

126 mg (75%) of target compound was obtained by using a method same asin Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg,0.289 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (83 mg, 0.289mmol), DIPEA (0.076 mL, 0.434 mmol) and NaBH(OAc)₃ (184 mg, 0.868 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.88-7.64 (m, 4H), 7.47-7.38 (m, 3H),7.37-7.24 (m, 5H), 7.24-7.19 (m, 2H), 7.19-7.04 (m, 4H), 6.60 (s, 1H),3.81-3.54 (m, 4H), 3.42-3.04 (m, 6H), 2.89 (t, 2H, J=6.8 Hz), 2.32-2.12(m, 2H)

Example 211-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 21)

91 mg (90%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-phenylpiperazine (0.033 mL, 0.222 mmol), DIPEA(0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.28 (m, 6H), 7.28-7.17 (m, 2H), 7.08(t, 1H, J=6.7 Hz), 6.65 (s, 1H), 3.94-3.48 (m, 8H), 3.44-3.33 (m, 2H),3.12-2.95 (m, 2H), 2.44 (s, 3H), 2.40-2.20 (m, 2H), 1.62 (s, 9H)

Example 221-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 22)

79 mg (76%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(2-fluorophenyl)piperazine (40 mg, 0.222 mmol),DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.48-7.19 (m, 4H), 7.09-6.84 (m, 4H), 6.54(s, 1H), 3.80-3.43 (m, 4H), 3.30-3.05 (m, 6H), 2.98-2.81 (m, 2H), 2.33(s, 3H), 2.30-2.13 (m, 2H), 1.51 (s, 9H)

Example 231-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 23)

82 mg (76%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(4-chlorophenyl)piperazine (60 mg, 0.222 mmol),DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.21 (m, 6H), 7.11-6.95 (m, 2H), 6.65(s, 1H), 3.97-3.56 (m, 4H), 3.50-3.17 (m, 6H), 3.11-2.90 (m, 2H), 2.44(s, 3H), 2.40-2.21 (m, 2H), 1.62 (s, 9H)

Example 241-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 24)

88 mg (82%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(2,4-dimethylphenyl)piperazine (42 mg, 0.222mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.28 (m, 4H), 7.09-6.97 (m, 3H), 6.62(s, 1H), 3.90-3.57 (m, 2H), 3.56-3.32 (m, 4H), 3.27-3.16 (m, 4H),3.10-2.96 (m, 2H), 2.44 (s, 3H), 2.40-2.27 (m, 2H), 2.31 (s, 3H), 2.25(s, 3H), 1.61 (s, 9H)

Example 251-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 25)

89 mg (84%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(3,4-dimethylphenyl)piperazine (42 mg, 0.222mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.30 (m, 4H), 7.22-7.07 (m, 3H), 6.62(s, 1H), 3.91-3.60 (m, 8H), 3.52-3.39 (m, 2H), 3.11-2.97 (m, 2H), 2.43(s, 3H), 2.40-2.30 (m, 2H), 2.30 (s, 3H), 2.25 9s, 3H), 1.60 (s, 9H)

Example 261-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 26)

82 mg (77%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(2,3-dimethylphenyl)piperazine (42 mg, 0.222mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (br s, 1H), 7.27-7.16 (m, 4H), 7.05(t, 1H, J=7.5 Hz), 6.94-6.81 (m, 2H), 5.98 (s, 1H), 3.58-3.47 (m, 2H),3.24-3.11 (m, 4H), 3.11-3.01 (m, 4H), 2.58 (t, 2H, J=7.1 Hz), 2.33 (s,3H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11-2.00 (m, 2H), 1.34 (s, 9H)

Example 271-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 27)

77 mg (72%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(4-methoxyphenyl)piperazine (43 mg, 0.222 mmol),DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (br s, 1H), 9.72 (br s, 1H), 7.25-7.16(m, 4H), 7.05 (d, 2H, J=8.2 Hz), 6.88 (d, 2H, J=8.4 Hz), 5.99 (s, 1H),3.68 (s, 3H), 3.64-3.49 (m, 4H), 3.29-3.11 (m, 4H), 2.58 (t, 2H, J=6.9Hz), 2.33 (s, 3H), 2.13-2.01 (m, 2H), 1.34 (s, 9H)

Example 284-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 28)

71 mg (66%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 2-methyl-1-m-tolylpiperazine (42 mg, 0.222 mmol),DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.68-7.41 (m, 3H), 7.41-7.20 (m, 5H), 6.60(s, 1H), 4.46 (bs, 1H), 4.28-4.10 (m, 1H), 4.06-3.76 (m, 4H), 6.76-3.60(m, 1H), 3.60-3.33 (m, 2H), 3.13-2.92 (m, 2H), 2.53-2.20 (m, 2H), 2.24(s, 6H), 1.59 (s, 9H), 1.27-1.10 (m, 3H)

Example 291-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 29)

99 mg (85%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(3,4-dichlorophenyl)piperazine (51 mg, 0.222mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (bs, 1H), 11.37 (bs, 1H), 7.43 (d, 1H,J=8.6 Hz), 7.26-7.13 (m, 5H), 6.98 (d, 1H, J=8.5 Hz), 3.90-3.78 (m, 2H),3.56-3.43 (m, 2H), 3.30-3.19 (m, 2H), 3.19-2.98 (m, 4H), 2.60-2.49 (m,2H), 2.48 (s, 3H), 2.33 (s, 3H), 2.12-1.97 (m, 2H), 1.34 (s, 9H)

Example 301-(3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 30)

111 mg (86%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal(60 mg, 0.222 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (64 mg,0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)₃ (141 mg, 0.666mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.30-7.59 (m, 4H), 7.36-7.10 (m, 8H), 5.94(s, 1H), 4.01-2.88 (m, 10H), 2.62-2.49 (m, 2H), 2.48 (s, 3H), 2.32 (s,3H), 2.02-1.91 (m, 2H), 1.32 (s, 9H)

Example 311-phenyl-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 31)

116 mg (89%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-phenylpiperazine (0.041 mL, 0.276 mmol), DIPEA (0.072mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.62-7.44 (m, 5H), 7.41 (d, 2H, J=7.0 Hz),7.32 (d, 2H, J=7.4 Hz), 7.25-7.11 (m, 5H), 6.95 (s, 1H), 3.98-3.53 (m,8H), 3.52-3.40 (m, 2H), 3.11-2.98 (m, 2H), 2.53-2.38 (m, 2H), 2.34 (s,3H)

Example 321-(2-fluorophenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 32)

105 mg (77%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(2-fluorophenyl)piperazine (50 mg, 0.276 mmol), DIPEA(0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (bs, 1H), 7.40-7.28 (m, 3H), 7.26-7.19(m, 2H), 7.19-7.02 (m, 7H), 7.02-6.97 (m, 1H), 6.51 (s, 1H), 3.60-3.52(m, 2H), 3.49-3.39 (m, 2H), 3.27-3.09 (m, 6H), 2.70 (t, 2H, J=7.3 Hz),2.27 (s, 3H), 2.21-2.09 (m, 2H)

Example 331-(4-chlorophenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 33)

73 mg (52%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(4-chlorophenyl)piperazine (74 mg, 0.276 mmol), DIPEA(0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.63-7.42 (m, 5H), 7.31-7.17 (m, 6H),7.13-7.05 (m, 2H), 7.02 (s, 1H), 4.01-3.65 (m, 4H), 3.54-3.21 (m, 6H),3.14-2.99 (m, 2H), 2.50-2.37 (m, 2H), 2.34 (s, 3H)

Example 341-(2,4-dimethylphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 34)

113 mg (82%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(2,4-dimethylphenyl)piperazine (53 mg, 0.276 mmol),DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (bs, 1H), 7.40-7.30 (m, 3H), 7.23 (d,2H, J=7.7 Hz), 7.14 (d, 2H, J=7.9 Hz), 7.08 (d, 2H, J=8.0 Hz), 7.00-6.88(m, 3H), 6.51 (s, 1H), 3.60-3.48 (m, 2H), 3.28-3.09 (m, 4H), 3.09-2.09(m, 4H), 2.71 (t, 2H, J=7.3 Hz), 2.27 (s, 3H), 2.22-2.03 (m, 2H), 2.20(s, 6H)

Example 351-(3,4-dimethylphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 35)

118 mg (85%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(3,4-dimethylphenyl)piperazine (53 mg, 0.276 mmol),DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.20 (bs, 1H), 7.40-3.27 (m, 3H), 7.23-7.16(m, 2H), 7.13 (d, 2H, J=7.8 Hz), 7.08 (d, 2H, J=7.7 Hz), 7.00 (d, 1H,J=8.1 Hz), 6.82 (s, 1H), 6.73 (d, 1H, J=7.5 Hz), 6.51 (s, 1H), 3.77-3.60(m, 2H), 3.60-3.47 (m, 2H), 3.24-3.01 (m, 6H), 2.70 (t, 2H, J=7.0 Hz),2.27 (s, 3H), 2.22-2.10 (m, 2H), 2.16 (s, 3H), 2.11 (s, 3H)

Example 361-(2,3-dimethylphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 36)

104 mg (75%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(2,3-dimethylphenyl)piperazine (53 mg, 0.276 mmol),DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.42 (m, 3H), 7.42-7.30 (m, 2H),7.20-7.10 (m, 4H), 7.07 (t, 1H, J=7.5 Hz), 6.95 (d, 1H, J=7.3 Hz), 6.89(d, 1H, J=7.6 Hz), 6.70 (s, 1H), 3.83-3.58 (m, 2H), 3.48-3.31 (m, 4H),3.21-3.10 (m, 2H), 3.10-2.99 (m, 2H), 2.99-2.87 (m, 2H), 2.39-2.29 (m,2H), 2.32 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H)

Example 371-(4-methoxyphenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 37)

108 mg (78%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(4-methoxyphenyl)piperazine (53 mg, 0.276 mmol),DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (bs, 1H), 7.44-7.26 (m, 3H), 7.22 (d,2H, J=7.0 Hz), 7.17-6.99 (m, 6H), 6.89 (d, 2H, J=7.1 Hz), 6.51 (s, 1H),3.69 (s, 3H), 3.61-3.50 (m, 4H), 3.38-3.12 (m, 6H), 2.80-2.60 (m, 2H),2.26 (s, 3H), 2.20-2.08 (m, 2H)

Example 382-methyl-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine(Compound 38)

112 mg (81%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 2-methyl-1-m-tolylpiperazine (53 mg, 0.276 mmol), DIPEA(0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.40 (m, 2H), 7.40-7.24 (m, 4H), 7.22(d, 2H, J=7.1 Hz), 7.13 (s, 2H, J=7.8 Hz), 7.08 (d, 2H, J=7.6 Hz), 6.51(s, 1H), 4.47-4.20 (m, 1H), 4.13-3.83 (m, 2H), 3.83-3.71 (m, 1H),3.71-3.49 (m, 3H), 3.49-3.10 (m, 4H), 2.80-2.62 (m, 2H), 2.34 (s, 3H),2.26 (s, 6H)

Example 391-(3,4-dichlorophenyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 39)

114 mg (76%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(3,4-dichlorophenyl)piperazine (64 mg, 0.276 mmol),DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (bs, 1H), 7.43 (d, 1H, J=8.8 Hz),7.40-7.29 (m, 3H), 7.29-7.14 (m, 3H), 7.13 (d, 2H, J=7.6 Hz), 7.07 (d,2H, J=7.8 Hz), 6.98 (d, 1H, J=8.8 Hz), 6.50 (s, 1H), 3.91-3.80 (m, 2H),3.60-3.48 (m, 2H), 3.30-3.13 (m, 4H), 3.13-3.00 (m, 2H), 2.73-2.61 (m,2H), 2.26 (s, 3H), 2.20-2.10 (m, 2H)

Example 401-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 40)

150 mg (91%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80mg, 0.276 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (80 mg, 0.276mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)₃ (175 mg, 0.828 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (bs, 1H), 7.39-7.14 (m, 6H), 7.14-7.00(m, 8H), 7.00-6.95 (m, 2H), 6.90-6.80 (m, 1H), 6.51 (s, 1H), 6.48 (s,1H), 3.84-3.50 (m, 4H), 3.50-3.29 (m, 2H), 3.29-3.03 (m, 4H), 2.79-2.60(m, 3H), 2.26 (s, 3H), 2.21-2.02 (m, 2H)

Example 411-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 41)

125 mg (90%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-phenylpiperazine (0.045 mL, 0.297 mmol), DIPEA (0.078 mL,0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.29-7.17 (m, 4H), 7.00-6.90 (m, 4H), 6.86(t, 1H, J=7.3 Hz), 6.23 (s, 1H), 3.90-3.46 (m, 4H), 3.78 (s, 3H),3.40-2.99 (m, 6H), 2.80 (t, 2H, J=7.5 Hz), 2.22-2.10 (m, 2H), 1.44 (s,9H)

Example 421-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 42)

132 mg (91%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(2-fluorophenyl)piperazine (54 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.43 (d, 2H, J=7.7 Hz), 7.18-7.00 (m, 6H),6.62 (s, 1H), 3.87 (s, 3H), 3.80-3.69 (m, 2H), 3.65-3.52 (m, 2H),3.40-3.18 (m, 6H), 2.32 (t, 2H, J=7.5 Hz), 1.61 (s, 9H)

Example 431-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 43)

82 mg (55%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(4-chlorophenyl)piperazine (80 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.41 (dd, 2H, J=6.7 Hz, J=2.1 Hz), 7.27 (dd,2H, J=6.8 Hz, J=2.2 Hz), 7.08 (dd, 2H, J=6.7 Hz, J=2.1 Hz), 7.02 (dd,2H, J=6.9 Hz, J=2.2 Hz), 6.60 (s, 1H), 3.88 (s, 3H), 3.88-3.61 (m, 4H),3.40-3.11 (m, 6H), 3.01 (t, 2H, J=7.7 Hz), 2.38-2.26 (m, 2H), 1.60 (s,9H)

Example 441-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 44)

109 mg (74%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(2,4-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.29 (d, 2H, J=8.6 Hz), 7.05-6.92 (m, 5H),6.20 (s, 1H), 3.84 (s, 3H), 3.72-3.60 (m, 2H), 3.39-3.25 (m, 4H), 2.83(t, 2H, J=7.5 Hz), 2.28 (s, 3H), 2.25 (s, 3H), 2.22-2.12 (m, 2H), 1.48(s, 9H)

Example 451-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 45)

118 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(3,4-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.38 (dd, 2H, J=6.7 Hz, J=2.0 Hz), 7.10 (d,1H, J=8.3 Hz), 7.05 (d, 2H, J=6.8 Hz), 6.97 (s, 1H), 6.88 (d, 1H, J=8.2Hz), 6.48 (s, 1H), 3.87 (s, 3H), 3.72-3.43 (m, 8H), 3.40-3.30 (m, 2H),2.96 (t, 2H, J=7.6 Hz), 2.37-2.25 (m, 2H), 2.28 (s, 3H), 2.21 (s, 3H),1.57 (s, 9H)

Example 461-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 46)

118 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(2,3-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.40-7.30 (m, 2H), 7.12-7.01 (m, 3H), 6.97(t, 2H, J=7.1 Hz), 6.44 (s, 1H), 3.87 (s, 3H), 3.78-3.60 (m, 2H),3.41-3.32 (m, 4H), 3.28-3.09 (m, 4H), 2.94 (t, 2H, J=7.6 Hz), 2.32-2.20(m, 2H), 2.26 (s, 3H), 2.23 (s, 3H), 1.56 (s, 9H)

Example 471-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 47)

107 mg (73%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(4-methoxyphenyl)piperazine (57 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.39 (d, 2H, J=6.7 Hz), 7.24 (d, 2H, J=9.0Hz), 7.06 (d, 2H, J=6.8 Hz), 6.95 (d, 2H, J=6.9 Hz), 6.52 (s, 1H), 3.87(s, 3H), 3.78 (s, 3H), 3.75-3.53 (m, 8H), 3.42-3.33 (m, 2H), 2.99 (t,2H, J=7.6 Hz), 2.39-2.24 (2H), 1.58 (s, 9H)

Example 484-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 48)

136 mg (92%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 2-methyl-1-m-tolylpiperazine (57 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.48-7.29 (m, 5H), 7.29-7.11 (m, 1H), 7.04(d, 2H, J=8.6 Hz), 6.41 (s, 1H), 4.33-4.17 (bs, 1H), 4.02-3.60 (m, 5H),3.60-3.50 (m, 1H), 3.50-3.37 (m, 2H), 2.95 (t, 2H, J=7.4 Hz), 2.40 (s,3H), 2.38-2.21 (m, 2H), 1.55 (s, 9H), 1.16 (d, 3H, J=6.4 Hz)

Example 491-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 49)

143 mg (89%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(3,4-dichlorophenyl)piperazine (69 mg, 0.297 mmol), DIPEA(0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.39 (d, 2H, J=8.9 Hz), 7.30-7.20 (m, 2H),7.20-7.15 (m, 1H), 7.00-6.92 (m, 3H), 6.14 (s, 1H), 3.95-3.80 (m, 2H),3.85 (s, 3H), 3.75-3.61 (m, 2H), 3.33-3.19 (m, 4H), 3.19-3.08 (m, 2H),2.80 (t, 2H, J=7.4 Hz), 2.26-2.10 (m, 2H), 1.47 (s, 9H)

Example 501-(3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 50)

141 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg,0.297 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (86 mg, 0.297mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)₃ (189 mg, 0.891 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.83-7.58 (m, 4H), 7.32 (d, 2H, J=6.7 Hz),7.19-7.05 (m, 4H), 7.01 (d, 2H, J=8.7 Hz), 6.32 (s, 1H), 5.30-5.00 (bs,1H), 3.85 (s, 3H), 3.78-3.52 (m, 4H), 3.40-3.00 (m, 6H), 2.87 (t, 2H,J=7.4 Hz), 2.28-2.10 (m, 2H), 1.51 (s, 9H)

Example 511-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 51)

88 mg (69%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261mmol), 1-phenylpiperazine (0.039 mL, 0.261 mmol), DIPEA (0.068 mL, 0.392mmol) and NaBH(OAc)₃ (166 mg, 0.783 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.61-7.40 (m, 5H), 7.40-7.29 (m, 2H),7.29-7.18 (m, 2H), 7.14 (d, 2H, J=7.5 Hz), 7.07-6.96 (m, 1H), 6.90 (d,2H, J=6.7 Hz), 6.82 (s, 1H), 3.79 (s, 3H), 3.98-3.09 (m, 10H), 3.07-2.89(m, 2H), 2.47-2.24 (m, 2H)

Example 521-(2-fluorophenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 52)

65 mg (53%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245mmol), 1-(2-fluorophenyl)piperazine (44 mg, 0.245 mmol), DIPEA (0.064mL, 0.368 mmol) and NaBH(OAc)₃ (156 mg, 0.735 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (br s, 1H), 7.43-7.27 (m, 3H), 7.23(d, 2H, J=6.0 Hz), 7.20-6.97 (m, 6H), 6.90 (d, 2H, J=6.9 Hz), 6.48 (s,1H), 3.73 (s, 3H), 3.67-3.52 (m, 2H), 3.52-3.40 (m, 2H), 3.30-3.10 (m,6H), 2.70 (t, 2H, J=7.1 Hz), 2.22-2.08 (m, 2H)

Example 531-(4-chlorophenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 53)

112 mg (82%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261mmol), 1-(4-chlorophenyl)piperazine (70 mg, 0.261 mmol), DIPEA (0.068mL, 0.392 mmol) and NaBH(OAc)₃ (166 mg, 0.783 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.53-7.42 (m, 3H), 7.40-7.32 (m, 2H), 7.26(d, 2H, J=8.7 Hz), 7.20 (d, 2H, J=8.6 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.88(d, 2H, J=8.4 Hz), 6.66 (s, 1H), 3.78 (s, 3H), 3.89-3.62 (m, 4H),3.42-3.32 (m, 2H), 3.29-3.16 (m, 2H), 3.11-2.98 (m, 2H), 2.94 (t, 2H,J=6.5 Hz), 2.38-2.22 (m, 2H)

Example 541-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 54)

104 mg (77%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261mmol), 1-(2,4-dimethylphenyl)piperazine (50 mg, 0.261 mmol), DIPEA(0.068 mL, 0.392 mmol) and NaBH(OAc)₃ (166 mg, 0.783 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.56-7.46 (m, 3H), 7.43-7.33 (m, 2H), 7.20(d, 2H, J=8.6 Hz), 7.07-6.96 (m, 2H), 6.96-6.83 (m, 3H), 6.66 (s, 1H),3.79 (s, 3H), 3.80-3.61 (m, 2H), 3.47-3.23 (m, 4H), 3.23-2.98 (m, 4H),2.95 (t, 2H, J=6.5 Hz), 2.37-2.17 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H)

Example 551-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 55)

105 mg (82%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245mmol), 1-(3,4-dimethylphenyl)piperazine (47 mg, 0.245 mmol), DIPEA(0.064 mL, 0.368 mmol) and NaBH(OAc)₃ (156 mg, 0.735 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (br s, 1H), 7.42-7.29 (m, 3H), 7.24(d, 2H, J=7.6 Hz), 7.13 (d, 2H, J=8.5 Hz), 7.06 (t, 1H, J=7.7 Hz),6.94-6.79 (m, 4H), 6.48 (s, 1H), 3.73 (s, 3H), 3.67-3.50 (m, 2H),3.32-3.12 (m, 4H), 3.12-2.98 (m, 4H), 2.71 (t, 2H, J=7.3 Hz), 2.28-2.09(m, 2H), 2.20 (s, 3H), 2.15 (s, 3H)

Example 561-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 56)

117 mg (93%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245mmol), 1-(2,3-dimethylphenyl)piperazine (47 mg, 0.245 mmol), DIPEA(0.064 mL, 0.368 mmol) and NaBH(OAc)₃ (156 mg, 0.735 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.56-7.30 (m, 5H), 7.30-7.10 (m, 2H),7.10-7.00 (m, 1H), 7.00-6.80 (m, 4H), 6.68 (s, 1H), 3.77 (s, 3H),3.75-3.58 (m, 2H), 3.49-3.23 (m, 4H), 3.23-3.01 (m, 4H), 3.00-2.85 (m,2H), 2.42-2.26 (m, 2H), 2.25 (m, 6H)

Example 571-(4-methoxyphenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 57)

81 mg (64%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245mmol), 1-(4-methoxyphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064mL, 0.368 mmol) and NaBH(OAc)₃ (156 mg, 0.735 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.64-7.48 (m, 7H), 7.34-7.21 (m, 2H),7.14-7.03 (m, 2H), 6.95 (s, 1H), 6.93-6.80 (m, 2H), 4.08-3.88 (m, 8H),3.83 (s, 3H), 3.79 (s, 3H), 3.59-3.42 (m, 2H), 3.12-2.99 (m, 2H),2.52-2.34 (m, 2H)

Example 584-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 58)

120 mg (89%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261mmol), 2-methyl-1-m-tolylpiperazine (50 mg, 0.261 mmol), DIPEA (0.068mL, 0.392 mmol) and NaBH(OAc)₃ (166 mg, 0.783 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.54-7.34 (m, 8H), 7.34-7.28 (m, 1H), 7.20(d, 2H, J=8.5 Hz), 6.89 (d, 2H, J=8.4 Hz), 6.68 (s, 1H), 4.32-4.19 (m,1H), 4.03-3.92 (m, 2H), 3.92-3.72 (m, 3H), 3.79 (s, 3H), 3.65-3.52 (m,1H), 3.52-3.42 (m, 2H), 3.07-2.91 (m, 2H), 2.42 (s, 3H), 2.41-2.29 (m,2H), 1.17 (d, 3H, J=3.1 Hz)

Example 591-(3,4-dichlorophenyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 59)

104 mg (76%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245mmol), 1-(3,4-dichlorophenyl)piperazine (57 mg, 0.245 mmol), DIPEA(0.064 mL, 0.368 mmol) and NaBH(OAc)₃ (156 mg, 0.735 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (br s, 1H), 7.43-7.27 (m, 3H), 7.23(d, 2H, J=6.0 Hz), 7.20-6.97 (m, 6H), 6.90 (d, 2H, J=6.9 Hz), 6.48 (s,1H), 3.73 (s, 3H), 3.67-3.52 (m, 2H), 3.52-3.40 (m, 2H), 3.30-3.10 (m,6H), 2.70 (t, 2H, J=7.1 Hz), 2.22-2.08 (m, 2H)

Example 601-(bis(4-fluorophenyl)methyl)-4-(3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 60)

127 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (75 mg, 0.261 mmol),DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)₃ (166 mg, 0.783 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.81-7.59 (m, 4H), 7.53-7.39 (m, 3H),7.37-7.22 (m, 2H), 7.21-7.06 (m, 6H), 6.86 (d, 2H, J=8.4 Hz), 6.55 (s,1H), 5.20-4.92 (bs, 1H), 3.77 (s, 3H), 3.73-3.52 (m, 4H), 3.41-2.98 (m,6H), 2.88 (t, 2H, J=6.3 Hz), 2.32-2.16 (m, 2H)

Example 611-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 61)

116 mg (89%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-phenylpiperazine (0.041 mL, 0.275 mmol), DIPEA (0.072 mL,0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.47-7.37 (m, 4H), 7.25 (t, 2H, J=7.6 Hz),7.11 (d, 2H J=8.2 Hz), 6.97 (t, 1H, J=7.2 Hz), 6.51 (s, 1H), 3.82-3.36(m, 8H), 3.33-3.22 (m, 2H), 2.98-2.86 (m, 2H), 2.29-2.12 (m, 2H), 1.48(s, 9H)

Example 621-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 62)

105 mg (78%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(2-fluorophenyl)piperazine (50 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.33 (m, 4H), 7.07-6.91 (m, 4H), 6.48(s, 1H), 3.70-3.56 (m, 2H), 3.56-3.43 (m, 2H), 3.32-3.20 (m, 4H),3.18-3.04 (m, 2H), 2.94-2.80 (m, 2H), 2.23-2.10 (m, 2H), 1.48 (s, 9H)

Example 631-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 63)

111 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(4-chlorophenyl)piperazine (74 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.48-7.34 (m, 4H), 7.14 (d, 2H, J=8.6 Hz),6.92 (d, 2H, J=8.7 Hz), 6.53 (s, 1H), 3.88-3.46 (m, 4H), 3.31-3.01 (m,6H), 2.93-2.82 (m, 2H), 2.23-2.12 (m, 2H), 1.47 (s, 1H)

Example 641-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 64)

115 mg (84%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(2,4-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.61-7.48 (m, 4H), 7.110-7.01 (m, 3H), 6.65(s, 1H), 3.88-3.60 (m, 2H), 3.54-3.21 (m, 8H), 3.08-3.01 (m, 2H),2.38-2.28 (m, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.61 (s, 9H)

Example 651-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 65)

199 mg (87%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(3,4-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.36 (m, 4H), 7.13-7.09 (m, 2H),7.07-6.99 (m, 1H), 6.45 (s, 1H), 3.78-3.57 (m, 8H), 3.36-3.26 (m, 2H),2.94-2.82 (m, 2H), 2.29-2.17 (m, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 1.47(s, 9H)

Example 661-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 66)

118 mg (85%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(2,3-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.48-7.36 (m, 4H), 6.97 (t, 1H, J=7.7 Hz),6.91-6.81 (m, 2H), 6.50 (s, 1H), 3.70-3.49 (m, 2H), 3.33-3.23 (m, 4H),3.17-3.06 (m, 4H), 2.93-2.87 (m, 2H), 2.27-2.19 (m, 2H), 2.10 (s, 6H),1.48 (s, 9H)

Example 671-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 67)

104 mg (75%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(4-methoxyphenyl)piperazine (53 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49 (d, 2H, J=7.8 Hz), 7.42 (d, 2H, J=8.1Hz), 7.16 (d, 2H, J=8.5 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.32 (s, 1H), 3.77(s, 3H), 3.60-3.43 (m, 8H), 3.40-3.32 (m, 2H), 2.87 (t, 2H, J=6.6 Hz),2.31-2.17 (m, 2H), 1.51 (s, 9H)

Example 684-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 68)

106 mg (77%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 2-methyl-1-m-tolylpiperazine (52 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.54-7.47 (m, 1H), 7.47-7.33 (m, 6H),7.30-7.21 (m, 1H), 6.43 (s, 1H), 4.41-4.30 (m, 1H), 4.13-4.01 (m, 1H),3.97-3.87 (m, 1H), 3.87-3.72 (m, 3H), 3.67-3.52 (m, 2H), 2.92-2.81 (m,2H), 2.34 (s, 3H), 2.30-2.17 (m, 2H), 1.47 (s, 9H), 1.12 (d, 3H, J=6.0Hz)

Example 691-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 69)

134 mg (90%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(3,4-dichlorophenyl)piperazine (64 mg, 0.275 mmol), DIPEA(0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.46-7.33 (m, 4H), 7.22 (d, 1H, J=8.8 Hz),7.04 (s, 1H), 6.82 (d, 1H, J=8.9 Hz), 6.53 (s, 1H), 3.80-3.63 (m, 2H),3.63-3.49 (m, 2H), 3.27-3.17 (m, 2H), 3.17-3.01 (m, 4H), 2.92-2.83 (m,2H), 2.23-2.09 (m 2H), 1.46 (s, 9H)

Example 701-(3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 70)

123 mg (75%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg,0.275 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (79 mg, 0.275mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)₃ (175 mg, 0.825 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.84-7.73 (m, 4H), 7.43 (d, 2H, J=7.5 Hz),7.38 (d, 2H, J=8.1 Hz), 7.17-7.05 (m, 4H), 6.42 (s, 1H), 5.57 (s, 1H),3.80-3.64 (m, 4H), 3.50-3.38 (m, 4H), 3.33-3.21 (m, 2H), 2.91-2.80 (m,2H), 2.23-2.07 (m, 2H), 1.45 (s, 9H)

Example 711-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 71)

121 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (100 mg, 0.307mmol), 1-phenylpiperazine (0.046 mL, 0.307 mmol), DIPEA (0.080 mL, 0.461mmol) and NaBH(OAc)₃ (195 mg, 0.921 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.46-7.35 (m, 3H), 7.35-7.24 (m, 6H), 7.22(d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.6 Hz), 6.98-6.90 (m, 1H), 6.60 (s,1H), 3.91-3.63 (m, 4H), 3.39-3.20 (m, 4H), 3.11-2.94 (m, 2H), 2.91 (t,2H, J=7.1 Hz), 2.33-2.20 (m, 2H)

Example 721-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 72)

108 mg (83%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257mmol), 1-(2-fluorophenyl)piperazine (46 mg, 0.257 mmol), DIPEA (0.070mL, 0.386 mmol) and NaBH(OAc)₃ (163 mg, 0.771 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.39-7.33 (m, 3H), 7.33-7.24 (m, 2H), 7.22(d, 2H, J=8.1 Hz), 7.15 (d, 2H, J=8.4 Hz), 7.01-7.86 (m, 4H), 6.72 (s,1H), 3.63-3.52 (m, 2H), 3.47-3.39 (m, 2H), 3.30-3.17 (m, 4H), 3.09-2.06(m, 2H), 2.84 (t, 2H, J=6.5 Hz), 2.27-2.11 (m, 2H)

Example 731-(4-chlorophenyl)-4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 73)

77 mg (65%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (70 mg, 0.225mmol), 1-(4-chlorophenyl)piperazine (61 mg, 0.225 mmol), DIPEA (0.059mL, 0.338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.52-7.43 (m, 3H), 7.43-7.30 (m, 4H),7.30-7.20 (m, 4H), 7.04 (d, 2H, J=9.0 Hz), 6.84 (s, 1H), 3.93-3.62 (m,4H), 3.42-3.09 (m, 6H), 2.98 (t, 2H, J=7.3 Hz), 2.40-2.29 (m, 2H)

Example 741-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 74)

99 mg (74%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257mmol), 1-(2,4-dimethylphenyl)piperazine (49 mg, 0.257 mmol), DIPEA(0.070 mL, 0.386 mmol) and NaBH(OAc)₃ (163 mg, 0.771 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.52-7.41 (m, 3H), 7.39-7.28 (m, 4H), 7.25(d, 2H, J=8.3 Hz), 7.07 (s, 1H), 7.00 (d, 1H, J=8.4 Hz), 6.94 (d, 1H,J=8.1 Hz), 6.71 (s, 1H), 3.80-3.61 (m, 2H), 3.44-3.31 (m, 4H), 3.26-3.04(m, 4H), 2.94 (t, 2H, J=6.1 Hz), 3.47-3.25 (m, 2H), 2.29 (s, 3H), 2.26(s, 3H)

Example 751-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 75)

99 mg (84%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (70 mg, 0.225mmol), 1-(3,4-dimethylphenyl)piperazine (61 mg, 0.225 mmol), DIPEA(0.059 mL, 0.338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.40 (m, 3H), 7.40-7.30 (m, 4H),7.30-7.13 (m, 5H), 6.73 (s, 1H), 3.97-3.62 (m, 8H), 3.50-3.41 (m, 2H),2.95 (t, 2H, J=7.2 Hz), 2.41-2.30 (m, 2H), 2.30 (s, 3H), 2.26 (s, 3H)

Example 761-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 76)

89 mg (67%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257mmol), 1-(2,3-dimethylphenyl)piperazine (49 mg, 0.257 mmol), DIPEA(0.070 mL, 0.386 mmol) and NaBH(OAc)₃ (163 mg, 0.771 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.40-7.32 (m, 3H), 7.28-7.19 (m, 4H), 7.14(d, 2H, J=8.4 Hz), 6.98 (t, 1H, J=7.7 Hz), 6.87 (d, 1H, J=7.4 Hz), 6.78(d, 1H, J=7.9 Hz), 6.54 (s, 1H), 3.68-3.52 (m, 2H), 3.34-3.21 (m, 4H),3.14-3.02 (m, 2H), 2.98-2.88 (m, 2H), 2.84 (t, 2H, J=6.6 Hz), 2.28-2.20(m, 2H), 2.18 (s, 3H), 2.16 (s, 3H)

Example 771-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 77)

85 mg (63%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257mmol), 1-(4-methoxyphenyl)piperazine (50 mg, 0.257 mmol), DIPEA (0.070mL, 0.386 mmol) and NaBH(OAc)₃ (163 mg, 0.771 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.45 (d, 2H, J=8.8 Hz), 7.39-7.32 (m, 3H),7.30-7.24 (m, 2H), 7.24 (d, 2H, J=8.0 hz), 7.16 (d, 2H, J=8.2 Hz), 6.95(d, 2H, J=8.7 Hz), 6.69 (s, 1H), 3.89-3.71 (m, 8H), 3.70 (s, 3H),3.43-3.28 (m, 2H), 2.91-2.77 (m, 2H), 2.32-2.16 (m, 2H)

Example 784-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 78)

114 mg (85%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257mmol), 2-methyl-1-m-tolylpiperazine (49 mg, 0.257 mmol), DIPEA (0.070mL, 0.386 mmol) and NaBH(OAc)₃ (163 mg, 0.771 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.67 (s, 1H), 7.61 (d, 1H, J=8.0 Hz),7.56-7.44 (m, 4H), 7.44-7.34 (m, 3H), 7.36 (d, 2H, J=8.3 Hz), 7.28 (d,2H, J=8.4 Hz), 6.79 (s, 1H), 4.59 (m, 1H), 4.33-4.19 (m, 1H), 4.17-4.04(m, 1H), 4.04-3.89 (m, 3H), 3.84-3.72 (m, 1H), 3.57-3.42 (m, 2H), 2.99(t, 2H, J=6.3 Hz), 2.46 (s, 3H), 2.47-2.30 (m, 2H), 1.23 (d, 3H, J=6.1Hz)

Example 791-(3,4-dichlorophenyl)-4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 79)

125 mg (86%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257mmol), 1-(3,4-dichlorophenyl)piperazine (60 mg, 0.257 mmol), DIPEA(0.070 mL, 0.386 mmol) and NaBH(OAc)₃ (163 mg, 0.771 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.39-7.30 (m, 3H), 7.30-7.22 (m, 2H),7.22-7.17 (m, 3H), 7.14 (d, 2H, J=8.3 Hz), 6.99 (s, 1H), 6.79 (d, 1H,J=8.7 Hz), 6.73 (s, 1H), 3.78-3.61 (m 2H), 3.61-3.48 (m, 2H), 2.27-3.16(m, 2H), 3.16-3.07 (m, 2H), 3.07-2.94 (m, 2H), 2.88-2.72 (m, 2H),2.24-2.10 (m, 2H)

Example 801-(bis(4-fluorophenyl)methyl)-4-(3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 80)

158 mg (83%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (100 mg, 0.307mmol), 1-phenylpiperazine (88 mg, 0.307 mmol), DIPEA (0.080 mL, 0.461mmol) and NaBH(OAc)₃ (195 mg, 0.921 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.78-759, (m, 4H), 7.49-7.40 (m, 3H), 7.32(d, 2H, J=8.6 Hz), 7.29-7.24 (m, 2H), 7.20 (d, 2H, J=8.7 Hz), 7.18-7.08(m, 4H), 6.57 (s, 1H), 7.02-7.80 (bs, 1H), 3.78-3.48 (m, 4H), 3.39-3.32(m, 2H), 3.26-2.93 (m, 4H), 2.87 (t, 2H, J=7.1 Hz), 2.31-2.15 (m, 2H)

Example 811-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 81)

134 mg (80%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-phenylpiperazine (0.055 mL, 0.365 mmol), DIPEA (0.1 mL,0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.59-4.48 (m, 2H), 7.37-7.21 (m, 4H),7.13-7.08 (m, 2H), 7.03-6.97 (m, 1H), 6.55 (s, 1H), 3.93-3.40 (m, 8H),3.40-3.34 (m, 2H), 2.99 (t, 2H, J=7.6 Hz), 2.38-2.23 (m, 2H), 1.58 (s,9H)

Example 821-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 82)

142 mg (82%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(2-fluorophenyl)piperazine (66 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.62-7.53 (m, 2H), 7.30 (t, 2H, J=8.7 Hz),7.18-7.03 (m, 4H), 6.69 (s, 1H), 3.79-3.69 (m, 2H), 3.66-3.57 (m, 2H),3.43-3.36 (m, 4H), 3.35-3.21 (m, 2H), 3.05 (t, 2H, J=7.7 Hz), 2.39-2.28(m, 2H), 1.62 (s, 9H)

Example 831-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 83)

108 mg (60%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(4-chlorophenyl)piperazine (98 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.61-7.53 (m, 2H), 7.34-7.23 (m, 4H),7.09-7.00 (m, 2H), 6.65 (s, 1H), 3.98-3.58 (m, 4H), 3.41-3.13 (m, 6H),3.03 (t, 2H, J=7.6 Hz), 2.39-2.23 (m, 2H), 1.60 (s, 9H)

Example 841-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 84)

139 mg (79%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(2,4-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.63-7.53 (m, 2H), 7.30 (t, 2H, J=8.6 Hz),7.12-6.08 (m, 3H), 6.67 (s, 1H), 3.84-3.44 (m, 4H), 3.44-3.22 (m, 6H),3.05 (t, 2H, J=7.5 Hz), 2.40-2.30 (m, 2H), 2.34 (s, 3H), 2.27 (s, 3H),1.66 (s, 9H)

Example 851-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 85)

126 mg (71%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(3,4-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.49 (m, 2H), 7.32-7.22 (m, 2H),7.20-7.12 (m, 2H), 7.10-7.03 (m, 1H), 6.56 (s, 1H), 3.80-3.62 (m, 8H),3.48-3.37 (m, 2H), 3.00 (t, 2H, J=7.6 Hz), 2.38-2.28 (m, 2H), 2.29 (s,3H), 2.25 (s, 3H), 1.58 (s, 9H)

Example 861-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 86)

133 mg (75%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(2,3-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.47-7.38 (m, 2H), 7.23-7.17 (m, 2H),7.09-7.03 (m, 1H), 6.99-6.93 (m, 2H), 6.23 (s, 1H), 3.73-3.62 (m, 2H),3.42-3.18 (m, 6H), 3.18-3.06 (m, 2H), 2.84 (t, 2H, J=7.4 Hz), 2.27 (s,3H), 2.26 (s, 3H), 2.24-2.13 (m, 2H), 1.49 (s, 9H)

Example 871-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 87)

102 mg (58%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(4-methoxyphenyl)piperazine (71 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.49 (m, 2H), 7.41-7.33 (m, 2H),7.30-7.21 (m, 2H), 7.07-6.98 (m, 2H), 6.56 (s, 1H), 3.81 (s, 1H),3.80-3.69 (m, 8H), 3.47-3.39 (m, 2H) 3.00 (t, 2H, J=7.5 Hz), 2.39-2.23(m, 2H), 1.58 (s, 9H)

Example 884-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 88)

143 mg (81%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 2-methyl-1-m-tolylpiperazine (69 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.56-7.47 (m, 3H), 7.47-7.38 (m, 2H),7.35-7.29 (m, 1H), 7.29-7.20 (m, 2H), 6.45 (s, 1H), 4.36 (bs, 1H),4.13-3.93 (m, 2H), 3.93-3.74 (m, 3H), 3.69-3.56 (m, 1H), 3.51-3.40 (m,2H), 2.96 (t, 2H, J=7.5 Hz), 2.43 (s, 3H), 2.38-2.23 (m, 2H), 1.55 (s,9H), 1.19 (d, 3H, J=6.5 Hz)

Example 891-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 89)

162 mg (85%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(3,4-dichlorophenyl)piperazine (84 mg, 0.365 mmol), DIPEA(0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.51-7.43 (m, 2H), 7.39 (d, 1H, J=8.9 Hz),7.26-7.14 (m, 3H), 7.00-6.91 (m, 1H), 6.38 (s, 1H), 3.92-3.81 (m, 2H),3.77-3.68 (m, 2H), 3.38-3.31 (m, 2H), 3.29-3.12 (m, 4H), 2.90 (t, 2H,J=7.5 Hz), 2.40-2.20 (m, 2H), 1.53 (s, 9H)

Example 901-(3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 90)

172 mg (81%) of target compound was obtained by using a method same asin Example 1 by using3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg,0.365 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (105 mg, 0.365mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)₃ (232 mg, 1.095 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.92-7.70 (m, 4H), 7.51-7.40 (m, 2H),2.27-7.10 (m, 6H), 6.40 (s, 1H), 5.42 (bs, 1H), 3.83-3.61 (m, 4H),3.49-3.22 (m, 6H), 2.90 (t, 2H, J=7.5 Hz), 2.30-2.12 (m, 2H), 1.52 (s,9H)

Example 911-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 91)

49 mg (62%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (55 mg, 0.187mmol), 1-phenylpiperazine (0.026 mL, 0.170 mmol), DIPEA (0.030 mL, 0.170mmol) and NaBH(OAc)₃ (108 mg, 0.510 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.48-7.40 (m, 2H), 7.37-7.28 (m, 6H),7.12-7.04 (m, 3H), 7.04-7.01 (m, 1H), 7.01-6.96 (m, 2H), 6.68 (s, 1H),3.88-3.63 (m, 4H), 3.44-3.30 (m, 4H), 3.28-3.08 (m, 2H), 2.93 (t, 2H,J=7.1 hz), 2.31 (t, 2H, J=7.6 Hz)

Example 921-(2-fluorophenyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 92)

57 mg (70%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (55 mg, 0.187mmol), 1-(2-fluorophenyl)piperazine (0.027 mL, 0.170 mmol), DIPEA (0.030mL, 0.170 mmol) and NaBH(OAc)₃ (108 mg, 0.510 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.51-7.48 (m, 3H), 7.46-7.42 (m, 2H),7.40-7.34 (m, 2H), 7.13-7.08 (m, 6H), 6.85 (s, 1H), 3.83-3.68 (m, 2H),3.64-3.52 (m, 2H), 3.45-3.33 (m, 4H), 3.27-3.13 (m, 2H), 3.00 (t, 2H,J=9.7 Hz), 2.43-2.28 (m, 2H)

Example 931-(4-chlorophenyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 93)

100 mg (72%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272mmol), 1-(4-chlorophenyl)piperazine (73 mg, 0.272 mmol), DIPEA (0.071mL, 0.408 mmol) and NaBH(OAc)₃ (173 mg, 0.816 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.53-7.44 (m, 3H), 7.41-7.34 (m, 2H),3.34-2.98 (m, 2H), 7.27 (d, 2H, J=8.8 Hz), 7.13-7.05 (m, 2H), 7.01 (d,2H, J=8.9 Hz), 6.76 (s, 1H), 3.91-3.55 (m, 4H), 3.42-3.23 (m, 4H),3.19-3.01 (m, 2H), 2.96 (t, 2H, J=6.6 Hz), 2.39-2.23 (m, 2H)

Example 941-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 94)

96 mg (70%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272mmol), 1-(2,4-dimethylphenyl)piperazine (52 mg, 0.272 mmol), DIPEA(0.071 mL, 0.408 mmol) and NaBH(OAc)₃ (173 mg, 0.816 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.51-7.13 (m, 3H), 7.38-7.24 (m, 4H),7.12-7.03 (m, 2H), 7.03-6.93 (m, 2H), 6.91 (d, 1H, J=8.1 Hz), 6.66 (s,1H), 3.83-3.57 (m, 2H), 3.43-3.12 (m, 6H), 3.12-2.98 (m, 2H), 2.94 (t,2H, J=6.5 Hz), 2.38-2.23 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H)

Example 951-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 95)

60 mg (71%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (50 mg, 0.170mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.170 mmol), DIPEA(0.030 mL, 0.170 mmol) and NaBH(OAc)₃ (108 mg, 0.510 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.44 (m, 3H), 7.41-7.34 (m, 2H),7.34-7.28 (m, 3H), 7.27-7.20 (m, 2H), 7.13-7.03 (m, 2H), 6.78 (s, 1H),3.98-3.70 (m, 8H), 3.52-3.40 (m, 2H), 2.98 (t, 2H, J=7.3 Hz), 2.41-2.32(m, 2H), 2.32 (s, 3H), 2.23 (s, 3H)

Example 961-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 96)

42 mg (50%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (50 mg, 0.170mmol), 1-(2,3-dimethylphenyl)piperazine (32 mg, 0.170 mmol), DIPEA(0.030 mL, 0.170 mmol) and NaBH(OAc)₃ (108 mg, 0.510 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.47-7.38 (m, 3H), 7.34-7.20 (m, 4H),7.10-7.00 (m, 3H), 6.94 (d, 1H, J=7.3 Hz), 6.85 (d, 1H, J=7.8 Hz), 6.55(s, 1H), 3.78-3.60 (m, 2H), 3.40-3.20 (m, 4H), 3.20-3.09 (m, 2H),3.06-2.91 (m, 2H), 2.90 (t, 2H, J=6.7 Hz), 2.31-2.26 (m, 2H), 2.26 (s,3H), 2.23 (s, 3H)

Example 971-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 97)

80 mg (58%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272mmol), 1-(4-methoxyphenyl)piperazine (72 mg, 0.272 mmol), DIPEA (0.071mL, 0.408 mmol) and NaBH(OAc)₃ (173 mg, 0.816 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.40 (m, 5H), 7.40-7.34 (m, 2H),7.34-7.26 (m, 2H), 7.12-7.00 (m, 4H), 6.75 (s, 1H), 3.98-3.59 (m, 8H),3.82 (s, 3H), 3.52-3.38 (m, 2H), 3.02-2.88 (m, 2H), 2.42-2.27 (m, 2H)

Example 984-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 98)

54 mg (65%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (53 mg, 0.179mmol), 2-methyl-1-m-tolylpiperazine (32 mg, 0.179 mmol), DIPEA (0.033mL, 0.187 mmol) and NaBH(OAc)₃ (108 mg, 0.510 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.53-7.20 (m, 10H), 7.10-6.90 (m, 3H), 6.72(s, 1H), 4.36 (bs, 1H), 4.14-3.74 (m, 7H), 3.74-3.60 (m, 2H), 3.54-3.38(m, 3H), 3.22-2.86 (m, 4H), 2.42 (s, 3H), 2.40-2.20 (m, 2H), 1.26-0.98(m, 3H)

Example 991-(3,4-dichlorophenyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 99)

90 mg (61%) of target compound was obtained by using a method same as inExample 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272mmol), 1-(3,4-dichlorophenyl)piperazine (63 mg, 0.272 mmol), DIPEA(0.071 mL, 0.408 mmol) and NaBH(OAc)₃ (173 mg, 0.816 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.49-7.21 (m, 8H), 7.13 (s, 1H), 7.08 (t,2H, J=8.2 Hz), 6.93 (d, 2H, J=8.9 Hz), 6.65 (s, 1H), 3.90-3.78 (m, 2H),3.78-3.62 (m, 2H), 3.41-3.18 (m, 4H), 3.04 (t, 2H, J=11.99 Hz),2.97-2.86 (m, 2H), 2.37-2.20 (m, 2H)

Example 1001-(bis(4-fluorophenyl)methyl)-4-(3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 100)

113 mg (69%) of target compound was obtained by using a method same asin Example 1 by using3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (78 mg, 0.272 mmol),DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)₃ (173 mg, 0.816 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.90-7.66 (m, 4H), 7.49-7.39 (m, 3H),7.33-7.21 (m, 4H), 7.21-7.10 (m, 4H), 7.06 (t, 2H, J=8.6 Hz), 6.58 (s,1H), 5.26 (bs, 1H), 3.89-3.59 (m, 4H), 3.42-3.14 (m, 6H), 2.88 (t, 2H,J=6.6 Hz), 2.31-2.19 (m, 2H)

Example 1011-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 101)

81 mg (95%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-phenylpiperazine (0.029 mL, 0.191 mmol), DIPEA (0.050 mL,0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.75 (d, 1H, J=4.9 Hz), 7.49-7.33 (m, 3H),7.31 (d, 2H, J=7.9 Hz), 7.21-7.18 (m, 1H), 7.15 (t, 1H, J=7.2 Hz), 6.68(s, 1H), 3.93-3.52 (m, 8H), 3.43-3.37 (m, 2H), 3.04-2.91 (m, 2H),2.39-2.21 (m, 2H) 1.65 (s, 9H)

Example 1021-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 102)

77 mg (73%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(2-fluorophenyl)piperazine (34 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.73 (d, 1H, J=5.0 Hz), 7.38-7.30 (m, 1H),7.21-7.17 (m, 1H), 7.17-7.03 (m, 4H), 6.62 (s, 1H), 3.80-3.67 (m, 2H),3.67-3.54 (m, 2H), 3.42-3.31 (m, 4H), 3.28-3.18 (m, 2H), 3.01-2.90 (m,2H), 2.39-2.20 (m, 2H), 1.63 (s, 9H)

Example 1031-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 103)

77 mg (73%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(4-chlorophenyl)piperazine (34 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.75 (d, 1H, J=5.0 Hz), 7.41-7.32 (m, 1H),7.28 (d, 2H, J=8.4 Hz), 7.21-7.15 (m, 1H), 7.05 (d, 2H, J=8.6 Hz), 6.66(s, 1H), 3.96-3.59 (m, 4H), 3.45-3.12 (m, 6H), 3.02-2.90 (m, 2H),2.39-2.23 (m, 2H), 1.64 (s, 9H)

Example 1041-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 104)

79 mg (87%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(2,4-dimethylphenyl)piperazine (36 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.71 (d, 1H, J=5.0 Hz), 7.34-7.28 (m, 1H),7.21-7.13 (m, 1H), 7.07-6.94 (m, 3H), 6.58 (s, 1H), 3.83-3.57 (m, 2H),3.50-3.17 (m, 8H), 2.98-2.85 (m, 2H), 2.36-2.19 (m, 2H), 2.31 (s, 3H),2.26 (s, 3H), 1.67 (s, 9H)

Example 1051-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 105)

79 mg (88%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)(50 mg, 0.191 mmol), 1-(3,4-dimethylphenyl)piperazine (36 mg, 0.191mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.73 (d, 1H, J=5.0 Hz), 7.38-7.29 (m, 2H),7.29-7.23 (m, 2H), 7.21-7.16 (m, 1H), 6.63 (s, 1H), 4.00-3.88 (m, 4H),3.88-3.71 (m, 4H), 3.50-3.39 (m, 2H), 3.03-2.91 (m, 2H), 2.38-2.21 (m,2H), 2.23 (s, 3H), 2.28 (s, 3H), 1.63 (s, 9H)

Example 1061-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 106)

86 mg (96%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(2,3-dimethylphenyl)piperazine (36 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.73 (d, 1H, J=5.0 Hz), 7.39-7.30 (m, 1H),7.21-7.14 (m, 1H), 7.11-7.02 (m, 1H), 7.02-6.92 (m, 2H), 6.64 (s, 1H),3.80-3.59 (m, 2H), 3.49-3.31 (m, 4H), 3.28-3.12 (m, 4H), 3.00-3.88 (m,2H), 2.38-2.23 (m, 2H), 2.27 (s, 6H), 1.64 (s, 9H)

Example 1071-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 107)

60 mg (66%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(4-methoxyphenyl)piperazine (40 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.78 (d, 1H, J=4.7 Hz), 7.57 (d, 2H, J=8.4Hz), 7.38-7.28 (m, 1H), 7.21-7.13 (m, 1H), 7.07 (d, 2H, J=8.3 Hz), 6.23(s, 1H), 4.02-3.91 (m, 4H), 3.91-3.82 (m, 4H), 3.83 (s, 3H), 3.50-3.39(m, 2H), 3.02-2.90 (m, 2H), 2.40-2.23 (m, 2H), 1.63 (s, 9H)

Example 1084-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 108)

89 mg (99%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 2-methyl-1-m-tolylpiperazine (36 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.69 (d, 1H, J=5.1 Hz), 7.68-7.62 (m, 1H),7.61-7.53 (m, 1H), 7.51 (t, 1H, J=7.8 Hz), 7.41-7.34 (m, 1H), 7.31-7.23(m, 1H), 7.18-7.11 (m, 1H), 6.54 (s, 1H), 4.59-4.43 (m, 1H), 4.31-4.17(m, 1H), 4.11-4.00 (m, 1H), 4.00-3.86 (m, 3H), 3.80-3.69 (m, 1H), 3.48(t, 2H, J=7.0 Hz), 2.99-2.88 (m, 2H), 2.45 (s, 3H), 2.39-2.23 (m, 2H),1.60 (s, 9H), 1.23 (d, 3H, J=5.8 Hz)

Example 1091-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 109)

92 mg (94%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(3,4-dichlorophenyl)piperazine (44 mg, 0.191 mmol), DIPEA(0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.78 (d, 1H, J=5.0 Hz), 7.43-7.36 (m, 2H),7.23-7.18 (m, 2H), 7.01-6.92 (m, 1H), 6.75 (s, 1H), 3.97-3.80 (m, 2H),3.80-3.67 (m, 2H), 3.40-3.18 (m, 6H), 3.08-2.93 (m, 2H), 2.39-2.21 (m,2H), 1.67 (s, 9H)

Example 1101-(3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 110)

92 mg (84%) of target compound was obtained by using a method same as inExample 1 by using3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg,0.191 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (55 mg, 0.191mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)₃ (121 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 8.07-7.88 (m, 4H), 7.66 (d, 1H, J=4.5 Hz),7.32-7.21 (m, 4H), 7.16 (d, 1H, J=2.8 Hz), 7.08 (t, 1H, J=7.9 Hz), 6.15(s, 1H), 3.80-3.56 (m, 5H), 3.43-3.29 (m, 4H), 3.29-3.11 (m, 2H), 2.55(t, 2H, J=7.2 Hz), 2.10-1.91 (m, 2H), 1.39 (s, 9H)

Example 1111-phenyl-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 111)

63 mg (96%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-phenylpiperazine (0.021 mL, 0.142 mmol), DIPEA (0.040 mL, 0.213mmol) and NaBH(OAc)₃ (90 mg, 0.426 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.68-7.52 (m, 6H), 7.44 (t, 2H, J=7.8 Hz),7.37 (d, 2H, J=8.0 Hz), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.99 (s,1H), 3.99-3.55 (m, 8H), 3.49-3.99 (m, 2H), 2.99 (t, 2H, J=6.3 Hz),2.43-2.29 (m, 2H)

Example 1121-(2-fluorophenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 112)

62 mg (91%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(2-fluorophenyl)piperazine (26 mg, 0.142 mmol), DIPEA (0.040mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.51 (m, 3H), 7.51-7.47 (m, 3H),7.14-7.00 (m, 6H), 6.85 (s, 1H), 3.80-3.67 (m, 2H), 3.62-3.52 (m, 2H),3.40-3.27 (m, 4H), 3.20-3.08 (m, 2H), 2.95 (t, 2H, J=6.1 Hz), 2.39-2.23(m, 2H)

Example 1131-(4-chlorophenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 113)

55 mg (78%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(4-chlorophenyl)piperazine (38 mg, 0.142 mmol), DIPEA (0.040mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.66-7.52 (m, 2H), 7.29 (d, 2H, J=8.9 Hz),7.21-7.17 (m, 1H), 7.09-7.00 (m, 3H), 6.99 (s, 1H), 3.92-3.64 (m, 4H),3.42-3.13 (m, 6H), 2.98 (t, 2H, J=7.2 Hz), 2.42-2.26 (m, 2H)

Example 1141-(2,4-dimethylphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 114)

66 mg (95%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(2,4-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA(0.040 mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.70-7.58 (m, 5H), 7.58-7.51 (m, 1H),7.27-7.19 (m, 1H), 7.17-7.10 (m, 1H), 7.10-7.01 (m, 3H), 7.01 (s, 1H),3.90-3.68 (m, 2H), 3.65-3.51 (m, 2H), 3.48-3.36 (m, 6H), 3.08-2.93 (m,2H), 2.41-2.30 (m, 2H), 2.38 (s, 3H), 2.28 (s, 3H)

Example 1151-(3,4-dimethylphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 115)

54 mg (77%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(3,4-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA(0.040 mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.52 (m, 3H), 7.52-7.37 (m, 3H), 7.28(s, 1H), 7.26-7.13 (m, 2H), 7.06 (d, 1H, J=3.1 Hz), 7.02 (d, 1H, J=3.7Hz), 6.83 (s, 1H), 3.92-3.70 (m, 8H), 3.51-3.40 (m, 2H), 3.00-3.89 (m,2H), 3.39-3.29 (m, 2H), 2.31 (s, 3H), 2.27 (s, 3H)

Example 1161-(2,3-dimethylphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 116)

50 mg (71%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(2,3-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA(0.040 mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.52 (m, 3H), 7.52-7.43 (m, 3H),7.10-7.00 (m, 3H), 6.96 (d, 1H, J=7.4 Hz), 6.90 (d, 1H, J=7.8 Hz), 6.79(s, 1H), 3.80-3.63 (m, 2H), 3.46-3.37 (m, 4H), 3.30-3.18 (m, 2H),3.18-3.03 (m, 2H), 2.99-2.90 (m, 2H), 2.38-2.30 (m, 2H), 2.26 (s, 3H),2.25 (s, 3H)

Example 1171-(4-methoxyphenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 117)

53 mg (76%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(4-methoxyphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.59-7.51 (m, 3H), 7.51-7.42 (m, 3H), 7.39(d, 2H, J=8.7 Hz), 7.04-6.97 (m, 3H), 6.77 (s, 1H), 3.81 (s, 3H),3.80-3.60 (m, 8H), 3.48-3.39 (m, 2H), 2.98-2.88 (m, 2H), 2.40-2.24 (m,2H)

Example 1182-methyl-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine(Compound 118)

55 mg (79%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 2-methyl-1-m-tolylpiperazine (27 mg, 0.142 mmol), DIPEA (0.040mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.54 (s, 1H), 7.50-7.31 (m, 8H), 7.30-7.25(m, 1H), 6.97-6.90 (m, 1H), 6.90-6.83 (m, 1H), 6.72 (s, 1H), 4.46-7.30(m, 1H), 4.20-4.08 (m, 1H), 4.01-3.91 (m, 1H), 3.91-3.76 (m, 3H),3.72-3.60 (m, 2H), 3.36 (t, 2H, J=6.8 Hz), 2.90-2.78 (m, 2H), 2.32 (s,3H), 2.30-2.20 (m, 2H), 1.10 (d, 3H, J=4.9 Hz)

Example 1191-(3,4-dichlorophenyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 119)

51 mg (68%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(3,4-dichlorophenyl)piperazine (33 mg, 0.142 mmol), DIPEA(0.040 mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.64-7.55 (m, 5H), 7.55 (d, 1H, J=4.9 Hz),7.38 (d, 1H, J=8.8 Hz), 7.17 (s, 1H), 7.08-7.02 (m, 1H), 6.95 (s, 1H),3.93-3.80 (m, 2H), 3.80-3.68 (m, 2H), 3.40-3.22 (m, 4H), 3.20-3.08 (m,2H), 3.01-2.90 (m, 2H), 2.40-2.27 (m, 2H)

Example 1201-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propyl)piperazine(Compound 120)

65 mg (78%) of target compound was obtained by using a method same as inExample 1 by using3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (41 mg, 0.142 mmol),DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)₃ (90 mg, 0.573 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.97-7.75 (m, 4H), 7.59-7.49 (m, 3H),7.49-7.34 (m, 3H), 7.27-7.10 (m, 4H), 7.01-6.91 (m, 2H), 6.70 (s, 1H),5.52 (bs, 1H), 3.89-3.68 (m, 4H), 3.52-3.32 (m, 6H), 2.98-2.78 (m, 2H),2.31-1.13 (m, 2H)

Example 1211-phenyl-4-(3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 121)

60 mg (81%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propanal (44 mg,0.206 mmol), 1-phenylpiperazine (0.031 mL, 0.206 mmol), DIPEA (0.054 mL,0.310 mmol) and NaBH(OAc)₃ (131 mg, 0.621 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.57-7.42 (m, 5H), 7.26-7.21 (m, 2H), 6.96(d, 2H, J=7.9 Hz), 6.85 (t, 1H, J=7.3 Hz), 6.17 (s, 1H), 3.17-3.14 (m,4H), 2.71 (t, 2H, J=7.6 Hz), 2.64-2.60 (m, 4H), 2.47-2.42 (m, 2H), 2.28(s, 3H), 1.86-1.76 (m, 2H)

Example 1221-(2-fluorophenyl)-4-(3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 122)

85 mg (83%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propanal (58 mg,0.268 mmol), 1-(2-fluorophenyl)piperazine (52 mg, 0.289 mmol), DIPEA(0.070 mL, 0.403 mmol) and NaBH(OAc)₃ (171 mg, 0.805 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.55-7.42 (m, 5H), 7.07-6.99 (m, 4H), 6.17(s, 1H), 3.09-3.06 (m, 4H), 2.74-2.68 (m, 2H), 2.66-2.63 (m, 4H),2.49-2.44 (m, 2H), 2.27 (s, 3H), 1.86-1.76 (m, 2H)

Example 1231-phenyl-4-(3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 123)

41 mg (80%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propanal (31 mg,0.138 mmol), 1-phenylpiperazine (0.021 mL, 0.138 mmol), DIPEA (0.036 mL,0.206 mmol) and NaBH(OAc)₃ (88 mg, 0.414 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.58-7.43 (m, 5H), 7.27-7.21 (m, 2H),6.98-6.95 (m, 2H), 6.88-6.83 (m, 1H), 6.21 (s, 1H), 3.18-3.15 (m, 4H),2.74-2.62 (m, 8H), 2.50-2.45 (m, 2H), 1.88-1.78 (m, 2H), 1.28 (t, 3H,J=7.6 Hz)

Example 1241-(2-fluorophenyl)-4-(3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 124)

53 mg (98%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propanal (31 mg,0.138 mmol), 1-(2-fluorophenyl)piperazine (28 mg, 0.154 mmol), DIPEA(0.036 mL, 0.206 mmol) and NaBH(OAc)₃ (89 mg, 0.418 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.58-7.44 (m, 5H), 7.10-6.94 (m, 4H), 6.21(s, 1H), 3.09-3.06 (m, 4H), 2.74-2.62 (m, 8H), 2.49-2.44 (m, 2H),1.86-1.76 (m, 2H), 1.28 (t, 3H, J=7.6 Hz)

Example 1251-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-phenylpiperazine(Compound 125)

90 mg (98%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-phenylpiperazine (0.034 mL, 0.225 mmol), DIPEA (0.060mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.50-7.40 (m, 2H), 7.40-7.32 (m, 2H), 7.21(t, 1H, J=7.2 Hz), 6.74 (s, 1H), 3.99-3.50 (m, 10H), 3.43-3.31 (m, 2H),3.06-3.91 (m, 4H), 2.38-2.24 (m, 2H), 1.91-1.78 (m, 2H), 1.83 (s, 9H),1.18 (t, 3H, J=7.0 Hz)

Example 1261-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 126)

93 mg (97%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-(2-fluorophenyl)piperazine (41 mg, 0.225 mmol), DIPEA(0.060 mL, 0.338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.18-7.01 (m, 4H), 6.74 (s, 1H), 3.80-3.66(m, 2H), 3.66-3.53 (m, 2H), 3.42-3.20 (m, 6H), 3.06-2.89 (m, 4H),2.38-2.21 (m, 2H), 1.92-1.77 (m, 2H), 1.83 (s, 9H), 0.95 (t, 3H, J=7.4Hz)

Example 1271-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 127)

62 mg (63%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-(4-chlorophenyl)piperazine (0.034 mg, 0.225 mmol),DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.29 (d, 2H, J=7.5 Hz), 7.07 (d, 2H, J=7.7Hz), 6.74 (s, 1H), 3.97-3.58 (m, 4H), 3.48-3.18 (m, 6H), 3.09-2.90 (m,4H), 2.39-2.21 (m, 2H), 1.93-1.74 (m, 2H), 1.83 (s, 9H), 1.13-1.02 (m,3H)

Example 1281-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 128)

96 mg (98%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-(2,4-dimethylphenyl)piperazine (43 mg, 0.225 mmol),DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.23-7.13 (m, 1H), 7.13-7.02 (m, 2H), 6.75(s, 1H), 3.93-3.64 (m, 2H), 3.64-3.40 (m, 6H), 3.40-3.30 (m, 2H),3.08-3.90 (m, 4H), 2.39 (s, 3H), 2.38-2.21 (m, 2H), 2.28 (s, 3H),1.94-1.72 (m, 2H), 1.83 (s, 9H), 1.20-1.06 (m, 3H)

Example 1291-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 129)

95 mg (98%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-(3,4-dimethylphenyl)piperazine (43 mg, 0.225 mmol),DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.40 (s, 1H), 7.38-7.23 (m, 2H), 6.75 (s,1H), 4.06-3.91 (m, 4H), 3.91-3.70 (m, 4H), 3.50-3.37 (m, 2H), 3.10-2.94(m, 4H), 2.40-2.29 (m, 2H), 2.33 (s, 3H), 2.29 (s, 3H), 1.94-1.78 (m,2H), 1.83 (s, 9H), 1.17-1.04 (m, 3H)

Example 1301-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 130)

92 mg (94%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-(2,3-dimethylphenyl)piperazine (43 mg, 0.225 mmol),DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.14-7.04 (m, 1H), 7.04-6.92 (m, 2H), 6.74(s, 1H), 3.80-3.61 (m, 2H), 3.50-3.30 (m, 4H), 3.29-3.19 (m, 4H),3.03-2.90 (m, 4H), 2.38-2.21 (m, 8H), 1.88-1.74 (m, 11H), 1.16-1.03 (m,3H)

Example 1311-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 131)

70 mg (71%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 1-(4-methoxyphenyl)piperazine (44 mg, 0.225 mmol),DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.55 (d, 2H, J=8.5 Hz), 7.07 (d, 2H, J=8.3Hz), 6.74 (s, 1H), 4.01-3.90 (m, 4H), 3.90-3.79 (m, 4H), 3.83 (s, 3H),3.47-3.36 (m, 2H), 3.06-2.91 (m, 4H), 2.40-2.23 (m, 2H), 1.90-1.73 (m,2H), 1.83 (s, 9H), 1.12-1.03 (m, 3H)

Example 1324-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 132)

93 mg (95%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50mg, 0.225 mmol), 2-methyl-1-m-tolylpiperazine (43 mg, 0.225 mmol), DIPEA(0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.68-7.43 (m, 3H), 7.41-7.30 (m, 1H), 6.74(s, 1H), 4.50 (bs, 1H), 4.30-4.16 (m, 1H), 4.08-3.98 (m, 1H), 3.98-3.82(m, 3H), 3.79-3.69 (m, 1H), 3.52-3.40 (m, 3H), 3.09-2.93 (m, 4H), 2.45(s, 3H), 2.40-2.27 (m, 2H), 1.90-1.77 (m, 2H), 1.83 (s, 9H), 1.22 (d,3H, J=16.1 Hz), 1.11 (t, 3H, J=7.0 Hz)

Example 1331-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 133)

103 mg (97%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal(50 mg, 0.225 mmol), 1-(3,4-dichlorophenyl)piperazine (52 mg, 0.225mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.40 (d, 1H, J=8.6 Hz), 7.22 (s, 1H), 7.00(d, 1H, J=8.2 Hz), 6.75 (s, 1H), 3.98-3.82 (m, 2H), 3.79-3.66 (m, 2H),3.40-3.20 (m, 6H), 3.08-2.98 (m, 4H), 2.39-2.22 (m, 2H), 1.90-1.76 (m,2H), 1.84 (s, 9H), 1.20 (t, 3H, J=7.0 Hz)

Example 1341-(3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 134)

107 mg (90%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal(50 mg, 0.225 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (65 mg,0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)₃ (143 mg, 0.675mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 8.02-7.80 (m, 4H), 7.30-7.17 (m, 4H), 6.71(s, 1H), 5.65 (bs, 1H), 3.93-3.76 (m, 4H), 3.64-3.49 (m, 4H), 3.45-3.34(m, 2H), 3.05-2.90 (m, 4H), 2.36-2.19 (m, 2H), 1.90-1.74 (m, 2H), 1.82(s, 9H), 1.11 (t, 3H, J=6.4 Hz)

Example 1351-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-phenylpiperazine(Compound 135)

132 mg (73%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-phenylpiperazine (0.067 mL, 0.450 mmol), DIPEA(0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.45-7.34 (m, 4H), 7.19 (t, 1H, J=7.1 Hz),6.77 (s, 1H), 4.01-3.79 (m, 4H), 3.80-3.50 (m, 4H), 3.50-3.38 (m, 2H),3.26-3.11 (m, 2H), 2.80 (t, 2H, J=7.4 Hz), 2.46-2.28 (m, 2H), 1.83 (s,9H), 1.87-1.68 (m, 2H), 1.03 (t, 3H, J=7.2 Hz)

Example 1361-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(2-fluorophenyl)piperazine(Compound 136)

171 mg (90%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(2-fluorophenyl)piperazine (81 mg, 0.450 mmol),DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.19-7.02 (m, 4H), 6.77 (s, 1H), 3.82-3.74(m, 2H), 3.68-3.52 (m, 2H), 3.49-3.38 (m, 6H), 3.23-3.09 (m, 2H), 2.80(t, 2H, J=7.6 Hz), 2.42-2.29 (m, 2H), 1.83 (s, 9H), 1.87-1.69 (m, 2H),1.03 (t, 3H, J=7.3 Hz)

Example 1371-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(4-chlorophenyl)piperazine(Compound 137)

171 mg (87%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(4-chlorophenyl)piperazine (121 mg, 0.450 mmol),DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.28 (d, 2H, J=8.8 Hz), 7.06 (d, 2H, J=9.0Hz), 6.76 (s, 1H), 3.90-3.71 (m, 4H), 3.43-3.21 (m, 6H), 3.21-3.11 (m,2H), 2.80 (t, 2H, J=7.6 Hz), 2.41-2.30 (m, 2H), 1.82 (s, 9H), 1.88-1.72(m, 2H), 1.03 (t, 3H, J=7.3 Hz)

Example 1381-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(2,4-dimethylphenyl)piperazine(Compound 138)

164 mg (84%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(2,4-dimethylphenyl)piperazine (86 mg, 0.450mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.13-7.01 (m, 3H), 6.77 (s, 1H), 3.82-3.69(m, 2H), 3.50-3.28 (m, 8H), 2.82-2.14 (m, 2H), 2.80 (t, 2H, J=7.2 Hz),2.34 (s, 3H), 2.43-2.32 (m, 2H), 2.27 (s, 3H), 1.83 (s, 9H), 1.86-1.71(m, 2H), 1.03 (t, 3H, J=7.1 Hz)

Example 1391-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(3,4-dimethylphenyl)piperazine(Compound 139)

135 mg (69%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(3,4-dimethylphenyl)piperazine (86 mg, 0.450mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.41 (s, 1H), 7.36-7.23 (m, 2H), 6.77 (s,1H), 4.08-3.71 (m, 8H), 3.60-3.46 (m, 2H), 3.28-3.16 (m, 2H), 2.80 (t,2H, J=7.4 Hz), 2.42-2.31 (m, 2H), 2.34 (s, 3H), 2.29 (s, 3H), 1.83 (s,9H), 1.86-1.70 (m, 2H), 1.03 (t, 3H, J=7.2 Hz)

Example 1401-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(2,3-dimethylphenyl)piperazine(Compound 140)

158 mg (81%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(2,3-dimethylphenyl)piperazine (86 mg, 0.450mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.09 (t, 1H, J=7.7 Hz), 7.02-6.93 (m, 2H),6.77 (s, 1H), 3.79-3.70 (m, 2H), 3.49-3.34 (m, 4H), 3.37-3.29 (m, 4H),3.29-3.21 (m, 2H), 2.80 (t, 2H, J=7.4 Hz), 2.42-2.32 (m, 2H), 2.28 (2s,6H), 1.83 (s, 9H), 1.88-1.74 (m, 2H), 1.04 (t, 3H, J=7.2 Hz)

Example 1411-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(4-methoxyphenyl)piperazine(Compound 141)

162 mg (83%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(4-methoxyphenyl)piperazine (87 mg, 0.450 mmol),DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.59 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8Hz), 6.77 (s, 1H), 4.06-3.93 (m, 4H), 3.93-3.76 (m, 4H), 3.57-3.46 (m,2H), 3.28-3.17 (m, 2H), 2.81 (t, 2H, J=7.2 Hz), 2.46-2.31 (m, 2H), 1.83(s, 9H), 1.88-1.71 (m, 2H), 1.03 (t, 3H, J=7.1 Hz)

Example 1424-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-2-methyl-1-m-tolylpiperazine(Compound 142)

190 mg (98%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 2-methyl-1-m-tolylpiperazine (86 mg, 0.450 mmol),DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.73-7.34 (m, 4H), 6.77 (s, 1H), 4.60-4.48(m, 1H), 4.42-4.21 (m, 1H), 4.18-3.88 (m, 4H), 3.82-3.70 (m, 1H),3.61-3.49 (m, 2H), 3.28-3.18 (m, 2H), 2.80 (t, 2H, J=7.6 Hz), 2.45 (s,3H), 2.47-2.46 (m, 2H), 1.84 (s, 9H), 1.89-1.73 (m, 2H), 1.24 (d, 3H,J=6.4 Hz), 1.04 (t, 3H, J=7.3 Hz)

Example 1431-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(3,4-dichlorophenyl)piperazine(Compound 143)

199 mg (93%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(3,4-dichlorophenyl)piperazine (104 mg, 0.450mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.39 (d, 1H, J=8.4 Hz), 7.20 (s, 1H), 6.97(d, 1H, J=8.3 Hz), 6.74 (s, 1H), 3.97-3.80 (m, 2H), 3.80-3.68 (m, 2H),3.47-3.35 (m, 2H), 3.35-3.23 (m, 4H), 3.23-3.10 (m, 2H), 2.86-2.72 (m,2H), 2.42-2.24 (m, 2H), 1.82 (s, 9H), 1.89-1.69 (m, 2H), 1.03 (t, 3H,J=6.6 Hz)

Example 1441-(3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propyl)-4-(bis(4-fluorophenyl)methyl)piperazine(Compound 144)

239 mg (97%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal(100 mg, 0.450 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (130 mg,0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)₃ (286 mg, 1.350mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.94-7.81 (m, 4H), 7.32-7.14 (m, 4H), 6.71(s, 1H), 5.60 (br s, 1H), 4.93-4.76 (m, 4H), 3.65-3.50 (m, 4H),3.50-3.40 (m, 2H), 3.21-3.10 (m, 2H), 2.78 (t, 2H, J=7.6 Hz), 2.40-2.24(m, 2H), 1.81 (s, 9H), 1.88-1.70 (m, 2H), 1.01 (t, 3H, J=7.3 Hz)

Example 1451-phenyl-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 145)

96 mg (69%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 1-phenylpiperazine (0.050 mL, 0.330 mmol), DIPEA (0.090 mL,0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.78-7.63 (m, 5H), 7.42 (t, 2H, J=4.1 Hz),7.33 (d, 2H J=3.9 Hz), 7.17 (t, 1H, J=7.3 Hz), 6.84 (s, 1H), 3.97-3.55(m, 8H), 3.50-3.40 (m, 2H), 3.03 (t, 2H J=7.4 Hz), 2.68 (t, 2H, J=7.7Hz), 2.44-2.30 (m, 2H), 1.79-1.64 (m, 2H), 0.95 (t, 3H, J=7.3 Hz)

Example 1461-(2-fluorophenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 146)

96 mg (66%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 1-(2-fluorophenyl)piperazine (59 mg, 0.330 mmol), DIPEA(0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.78-7.60 (m, 5H), 7.20-7.02 (m, 4H), 6.76(s, 1H), 3.82-3.68 (m, 2H), 3.68-3.53 (m, 2H), 3.43-3.30 (m, 4H),3.30-3.16 (m, 2H), 2.99 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.6 Hz),2.40-2.26 (m, 2H), 1.78-1.62 (m, 2H), 0.95 (t, 3H, J=7.3 Hz)

Example 1471-(4-chlorophenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 147)

69 mg (45%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 1-(4-chlorophenyl)piperazine (89 mg, 0.330 mmol), DIPEA(0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.78-7.63 (m, 5H), 7.29 (d, 2H, J=3.4 Hz),7.06 (d, 2H, J=3.4 Hz), 6.82 (s, 1H), 3.98-3.60 (m, 4H), 3.48-3.14 (m,6H), 3.01 (t, 2H, J=7.6 Hz), 2.67 (t, 2H, J=7.7 Hz), 2.39-2.28 (m, 2H),1.79-1.62 (m, 2H), 0.95 (t, 3H, J=7.4 Hz)

Example 1481-(2,4-dimethylphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 148)

73 mg (49%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 1-(2,4-dimethylphenyl)piperazine (63 mg, 0.330 mmol), DIPEA(0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.70-7.49 (m, 5H), 7.06-6.82 (m, 3H), 6.51(s, 1H), 3.80-3.51 (m, 2H), 3.44-2.97 (m, 6H), 2.97-2.83 (m, 2H), 2.64(t, 2H, J=7.5 Hz), 2.38-2.16 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H),1.75-1.60 (m, 2H), 0.93 (t, 3H, J=7.2 Hz)

Example 1491-(3,4-dimethylphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 149)

159 mg (85%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (100mg, 0.413 mmol), 1-(3,4-dimethylphenyl)piperazine (79 mg, 0.413 mmol),DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.61-7.42 (m, 5H), 7.05 (d, 1H, J=8.2 Hz),6.84 (s, 1H), 6.76 (d, 1H, J=2.5 Hz), 6.34 (s, 1H), 3.80-3.10 (m, 10H),2.87 (t, 2H, J=7.2 Hz), 2.62 (t, 2H, J=7.7 Hz), 2.31-2.12 (m, 2H), 2.23(s, 3H), 2.19 (s, 3H), 1.70-1.50 (m, 2H), 0.91 (t, 3H, J=7.4 Hz)

Example 1501-(2,3-dimethylphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 150)

124 mg (66%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (100mg, 0.413 mmol), 1-(2,3-dimethylphenyl)piperazine (79 mg, 0.413 mmol),DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.67-7.47 (m, 5H), 7.07 (t, 1H, J=7.7 Hz),6.95 (d, 1H, J=7.4 Hz), 6.84 (d, 1H, J=7.9 Hz), 6.44 (s, 1H), 3.74-3.55(m, 2H), 3.50-3.23 (m, 4H), 3.23-3.10 (m, 2H), 3.10-2.96 (m, 2H), 2.91(t, 2H, J=7.1 Hz), 2.63 (t, 2H, J=7.6 Hz), 2.31-2.18 (m, 2H), 2.62 (s,3H), 2.24 (s, 3H), 1.71-1.57 (m, 2H), 0.92 (t, 3H, J=7.3 Hz)

Example 1511-(4-methoxyphenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 151)

42 mg (28%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 1-(4-methoxyphenyl)piperazine (64 mg, 0.330 mmol), DIPEA(0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.68-7.51 (m, 5H), 7.17 (d, 2H, J=8.7 Hz),6.95 (d, 2H, J=8.6 Hz), 6.60 (s, 1H), 3.79 (s, 3H), 3.68-3.43 (m, 8H),3.40-3.31 (m, 2H), 2.95 (t, 2H, J=7.0 Hz), 2.65 (t, 2H, J=7.5 Hz),2.36-2.24 (m, 2H), 1.70-1.59 (m, 2H), 0.94 (t, 3H, J=7.2 Hz)

Example 1522-methyl-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)-1-m-tolylpiperazine(Compound 152)

68 mg (45%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 2-methyl-1-m-tolylpiperazine (63 mg, 0.330 mmol), DIPEA(0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.70-7.53 (m, 5H), 7.53-7.39 (m, 3H), 7.33(s, 1H), 6.63 (s, 1H), 4.42-4.29 (m, 1H), 4.42-4.21 (m, 1H), 4.13-3.74(m, 4H), 3.69-3.50 (m, 1H), 3.52-3.40 (m, 2H), 2.97 (t, 2H, J=7.3 Hz),2.66 (t, 2H, J=7.7 Hz), 2.43 (s, 3H), 2.42-2.30 (m, 2H), 2.76-2.64 (m,2H), 1.19 (d, 3H, J=6.5 Hz), 0.94 (t, 3H, J=7.3 Hz)

Example 1531-(3,4-dichlorophenyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 153)

77 mg (47%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg,0.330 mmol), 1-(3,4-dichlorophenyl)piperazine (76 mg, 0.330 mmol), DIPEA(0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.63-43 (m, 5H), 7.38 (d, 1H, J=8.9 Hz),7.11 (s, 1H), 6.92 (d, 1H, J=4.5 Hz), 6.34 (s, 1H), 3.91-3.80 (m, 2H),3.80-3.69 (m, 2H), 3.29-3.17 (m, 2H), 3.06-2.93 (m, 2H), 2.87 (t, 2H,J=7.0 Hz), 2.61 (t, 2H, J=7.6 Hz), 2.30-2.17 (m, 2H), 1.67-1.52 (m, 2H),0.91 (t, 3H, J=7.4 Hz)

Example 1541-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propyl)piperazine(Compound 154)

128 mg (71%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80mg, 0.330 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (95 mg, 0.330mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)₃ (210 mg, 0.990 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.96-7.76 (m, 4H), 7.72-7.52 (m, 5H),7.28-7.14 (m, 4H), 6.59 (s, 1H), 5.50 (br s, 1H), 3.88-3.69 (m, 4H),3.57-3.36 (m, 6H), 2.92 (t, 2H, J=7.3 Hz), 2.63 (t, 2H, J=7.6 Hz),2.35-2.20 (m, 2H), 1.69-1.56 (m, 2H), 0.92 (t, 3H, J=7.3 Hz)

Example 1551-phenyl-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 155)

153 mg (87%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100mg, 0.413 mmol), 1-phenylpiperazine (0.062 mL, 0.413 mmol), DIPEA (0.110mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (br s, 1H), 7.54-7.32 (m, 5H), 7.24(t, 2H, J=7.3 Hz), 6.98 (d, 2H, J=8.2 Hz), 6.90-6.79 (m, 1H), 6.24 (s,1H), 3.86-3.68 (m, 2H), 3.58-3.44 (m, 2H), 3.20-3.01 (m, 6H), 2.71 (t,2H, J=7.5 Hz), 2.61-2.43 (m, 2H), 2.16-2.02 (m, 2H), 1.71-1.55 (m, 2H),0.94 (t, 3H, J=7.3 Hz)

Example 1561-(2-fluorophenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 156)

151 mg (82%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100mg, 0.413 mmol), 1-(2-fluorophenyl)piperazine (74 mg, 0.413 mmol), DIPEA(0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.58-7.39 (m, 5H), 7.08-6.92 (m, 4H), 6.36(s, 1H), 3.62-3.45 (m, 4H), 3.20-3.01 (m, 6H), 2.80-2.68 (m, 2H), 2.59(t, 2H, J=7.5 Hz), 2.16-1.99 (m, 2H), 1.74-1.59 (m, 2H), 0.94 (t, 3H,J=7.3 Hz)

Example 1571-(4-chlorophenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 157)

118 mg (83%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75mg, 0.310 mmol), 1-(4-chlorophenyl)piperazine (83 mg, 0.310 mmol), DIPEA(0.081 mL, 0.465 mmol) and NaBH(OAc)₃ (197 mg, 0.930 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.57-7.42 (m, 5H), 7.18 (d, 2H, J=9.0 Hz),6.91 (d, 2H, J=9.0 Hz), 6.44 (s, 1H), 3.77-3.67 (m, 2H), 3.60-3.50 (m,2H), 3.18-2.98 (m, 6H), 2.72 (t, 2H, J=7.7 Hz), 2.62 (t, 2H, J=7.6 Hz),2.12-2.00 (m, 2H), 2.73-2.60 (m, 2H), 0.95 (t, 3H, J=7.4 Hz)

Example 1581-(2,4-dimethylphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 158)

134 mg (95%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75mg, 0.310 mmol), 1-(2,4-dimethylphenyl)piperazine (59 mg, 0.310 mmol),DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)₃ (197 mg, 0.930 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.40 (m, 5H), 7.05-6.90 (m, 3H), 6.31(s, 1H), 3.67-3.50 (m, 2H), 3.28-3.03 (m, 8H), 2.83-2.72 (m, 2H), 2.62(t, 2H, J=7.6 Hz), 2.27 (s, 3H), 2.25 (s, 3H), 2.18-2.02 (m, 2H),1.76-1.63 (m, 2H), 1.00 (t, 3H, J=7.4 Hz)

Example 1591-(3,4-dimethylphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 159)

172 mg (92%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100mg, 0.413 mmol), 1-(3,4-dimethylphenyl)piperazine (79 mg, 0.413 mmol),DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (br s, 1H), 7.57-7.30 (m, 5H), 6.99(d, 1H, J=8.2 Hz), 6.78 (s, 1H), 6.69 (d, 1H, J=4.2 Hz), 6.24 (s, 1H),3.79-3.60 (m, 2H), 3.60-3.40 (m, 2H), 3.20-2.94 (m, 6H), 2.78-2.62 (m,2H), 2.58-2.40 (m, 2H), 2.16 (s, 3H), 2.11 (s, 3H), 2.11-1.98 (m, 2H),1.69-1.57 (m, 2H), 0.94 (t, 3H, J=7.3 Hz)

Example 1601-(2,3-dimethylphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 160)

146 mg (78%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100mg, 0.413 mmol), 1-(2,3-dimethylphenyl)piperazine (79 mg, 0.413 mmol),DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (br s, 1H), 7.57-7.34 (m, 5H),7.12-6.98 (m, 1H), 6.94-6.81 (m, 2H), 6.24 (s, 1H), 3.58-3.40 (m, 2H),3.24-3.00 (m, 8H), 2.71 (t, 2H, J=7.4 Hz), 2.59-2.48 (m, 2H), 2.20 (s,3H), 2.14 (s, 3H), 2.12-2.00 (m, 2H), 1.70-1.58 (m, 2H), 0.94 (t, 3H,J=7.4 Hz)

Example 1611-(4-methoxyphenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 161)

122 mg (65%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100mg, 0.413 mmol), 1-(4-methoxyphenyl)piperazine (80 mg, 0.413 mmol),DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (br s, 1H), 7.57-7.28 (m, 5H), 6.94(d, 2H, J=8.6 Hz), 6.84 (d, 2H, J=8.9 Hz), 6.23 (s, 1H), 3.68 (s, 3H),3.64-3.44 (m, 4H), 3.19-2.93 (m, 6H), 2.78-2.62 (m, 2H), 2.59-2.40 (m,2H), 2.13-1.97 (m, 2H), 1.70-1.52 (m, 2H), 0.94 (t, 3H, J=7.3 Hz)

Example 1622-methyl-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)-1-m-tolylpiperazine(Compound 162)

132 mg (94%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75mg, 0.310 mmol), 2-methyl-1-m-tolylpiperazine (59 mg, 0.310 mmol), DIPEA(0.081 mL, 0.465 mmol) and NaBH(OAc)₃ (197 mg, 0.930 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.73-7.55 (m, 5H), 7.55-7.10 (m, 3H), 6.66(s, 1H), 4.24 (bs, 1H), 4.10-3.77 (m, 2H), 3.77-3.58 (m, 2H), 3.58-3.39(m, 1H), 2.85 (t, 2H, J=7.2 Hz), 2.75 (t, 2H, J=7.5 Hz), 2.40 (s, 3H),2.31-2.16 (m, 2H), 1.87-1.70 (m, 2H), 1.14 (d, 3H, J=6.1 Hz), 1.04 (t,3H, J=7.3 Hz)

Example 1631-(3,4-dichlorophenyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 163)

192 mg (94%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100mg, 0.413 mmol), 1-(3,4-dichlorophenyl)piperazine (95 mg, 0.413 mmol),DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)₃ (263 mg, 1.239 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (br s, 1H), 7.59-7.35 (m, 6H), 7.23(s, 1H), 6.98 (d, 1H, J=4.5 Hz), 6.23 (s, 1H), 3.93-3.77 (m, 2H),3.58-3.43 (m, 2H), 3.26-3.13 (m, 2H), 3.13-2.94 (m, 4H), 2.77-2.63 (m,2H), 2.55-2.40 (m, 2H), 2.13-1.98 (m, 2H), 1.69-1.52 (m, 2H), 0.93 (t,3H, J=7.3 Hz)

Example 1641-(bis(4-fluorophenyl)methyl)-4-(3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 164)

157 mg (92%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75mg, 0.310 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (89 mg, 0.310mmol), DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)₃ (197 mg, 0.930 mmol).

¹H NMR (400 MHz, MeOH-d₄) δ 7.83-7.66 (m, 4H), 7.66-7.50 (m, 5H),7.21-7.03 (m, 4H), 6.60 (s, 1H), 5.30-5.10 (bs, 1H), 3.74-3.47 (m, 4H),3.28-3.10 (m, 4H), 2.79 (t, 2H, J=7.5 Hz), 2.73 (t, 2H, J=7.6 Hz),2.21-2.08 (m, 2H), 1.83-1.68 (m, 2H), 1.02 (t, 3H, J=7.3 Hz)

Example 1651-(2-fluorophenyl)-4-(3-(1-(3-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 165)

91.87 mg (46.19%) of target compound was obtained by using a method sameas in Example 1 by using3-(1-(3-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (124.75 mg,0.451 mmol), 1-(2-fluorophenyl)piperazine (92 mL, 0.586 mmol), andNaCNBH3 (85.02 mg, 1.353 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.48 (d, 1H), 7.36-7.31 (m, 3H), 7.03-6.87 (m,4H), 6.04 (s, 1H), 3.07 (t, 4H), 2.69 (t, 2H), 2.66-2.57 (m, 6H),2.02-1.76 (m, 2H), 1.74-1.62 (m, 2H), 0.97 (t, 3H)

Example 1661-(2-fluorophenyl)-4-(3-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 166)

114 mg (66.0%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (107.73 mg,0.396 mmol), 1-(2-fluorophenyl)piperazine (82.22 mL, 0.514 mmol), andNaCNBH3 (74.58 mg, 1.187 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.31-7.29 (m, 2H), 7.04-6.89 (m, 6H), 6.00 (s,1H), 3.81 (s, 3H), 3.07 (t, 4H), 2.63-2.57 (m, 8H), 2.38 (t, 2H),1.83-1.78 (m, 2H), 1.75-1.61 (m, 2H), 0.97 (t, 3H)

Example 1671-(2-fluorophenyl)-4-(3-(1-(4-methylphenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 167)

93 mg (59.7%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-methylphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (95 mg, 0.371mmol), 1-(2-fluorophenyl)piperazine (76 mL, 0.482 mmol), and NaCNBH3 (70mg, 1.112 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.28 (d, 2H), 7.21 (d, 2H), 7.06-6.87 (m, 4H),6.01 (s, 1H), 3.06 (t, 4H), 2.67-2.58 (m, 4H), 2.54 (t, 3H), 2.36 (t,5H), 2.40-2.35 (m, 5H), 1.83-1.75 (m, 2H), 1.72-1.62 (m, 2H), 0.98 (t,3H)

Example 1681-(2-fluorophenyl)-4-(3-(1-(4-fluorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 168)

119 mg (65.0%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-fluorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (112.3 mg, 0.431mmol), 1-(2-fluorophenyl)piperazine (102.22 mL, 0.647 mmol), and NaCNBH3(274.29 mg, 1.294 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.39-7.34 (m, 2H), 7.14-7.08 (m, 2H),7.03-6.88 (m, 4H), 6.02 (s, 1H), 3.10 (t, 4H), 2.68 (t, 4H), 2.64-2.57(m, 4H), 2.50-2.45 (m, 2H), 1.85-1.80 (m, 2H), 1.71-1.64 (m, 2H), 0.97(t, 3H)

Example 1691-(2-fluorophenyl)-4-(3-(1-(4-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 169)

60 mg (82.3%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (45.74 mg, 0.165mmol), 1-(2-fluorophenyl)piperazine (39.16 mL, 0.247 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.34 (m, 4H), 7.04-6.88 (m, 4H), 6.04 (s,1H), 3.08 (t, 4H), 2.68-2.57 (m, 8H), 2.41 (t, 2H), 1.86-1.78 (m, 2H),1.76-1.62 (m, 2H), 0.97 (t, 3H)

Example 1701-(2-fluorophenyl)-4-(3-(1-(4-trifluorophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 170)

140 mg (84.8%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-trifluorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (108 mg,0.348 mmol), 1-(2-fluorophenyl)piperazine (82.5 mL, 0.522 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, 2H), 7.56 (d, 2H), 7.01-6.98 (m, 2H),6.94-6.87 (m, 2H), 6.08 (s, 1H), 3.08 (t, 4H), 2.71 (t, 2H), 2.63-2.58(m, 6H), 2.45 (t, 2H), 1.89-1.82 (m, 2H), 1.72-1.62 (m, 2H), 0.97 (t,3H)

Example 1711-(2-fluorophenyl)-4-(3-(1-(4-trifluoromethoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 171)

100 mg (80.6%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-trifluoromethoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (82.5mg, 0.253 mmol), 1-(2-fluorophenyl)piperazine (60 mL, 0.379 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.47-7.44 (m, 2H), 7.29-7.26 (m, 2H),7.02-6.88 (m, 4H), 6.04 (s, 1H), 3.05 (t, 4H), 2.67 (t, 2H), 2.60 (t,2H), 2.56-2.53 (m, 4H), 1.85-1.80 (m, 2H), 1.77-1.62 (m, 2H), 0.97 (t,3H)

Example 1721-(2-fluorophenyl)-4-(3-(1-(4-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 172)

70 mg (82.5%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propanal 54 mg, 0.188mmol), 1-(2-fluorophenyl)piperazine (39 mL, 0.244 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, 2H), 7.66 (d, 2H0, 7.03-6.89 (m, 4H),6.12 (s, 1H), 3.08 (m, 4H), 2.77 (t, 2H), 2.61 (m, 6H), 2.45 (t, 2H),1.96-1.82 (m, 2H), 1.74-1.62 (m, 2H), 0.98 (t, 3H)

Example 1731-(2-fluorophenyl)-4-(3-(1-benzyl-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 173)

86 mg (84.5%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-benzyl-3-propyl-1H-pyrazol-5-yl)propanal (62mg, 0.242 mmol), 1-(2-fluorophenyl)piperazine (76 mL, 0.484 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.29-7.20 (m, 3H), 7.03-6.88 (m, 6H), 5.89 (s,1H), 5.25 (s, 2H), 3.05 (t, 4H), 2.58 (t, 2H), 2.52-2.48 (m, 6H), 2.33(t, 2H), 1.78-1.60 (m, 4H), 0.96 (s, 3H)

Example 1741-(2-fluorophenyl)-4-(3-(1-(3-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 174)

67 mg (83.6%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(3-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (51 mg, 0.178mmol), 1-(2-fluorophenyl)piperazine (42 mL, 0.266 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.32 (t, 1H), 8.16 (m, 1H), 7.82 (m, 1H), 7.61(t, 1H), 7.00-6.93 (m, 2H), 6.91-6.88 (m, 2H), 6.10 (s, 1H), 3.06 (t,4H), 2.74 (t, 2H), 2.63-2.38 (m, 6H), 2.43 (t, 2H), 1.91-1.81 (m, 2H),1.75-1.63 (m, 2H), 0.98 (t, 3H)

Example 1751-(2-fluorophenyl)-4-(3-(1-(2′-pyridyl)-3-propyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 175)

100 mg (90.5%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(2′-pyridyl)-3-propyl-1H-pyrazol-5-yl)propanal (66 mg, 0.271 mmol),1-(2-fluorophenyl)piperazine (86 mL, 0.543 mmol), and NaBH(OAc)₃ (198mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.39-8.37 (m, 1H), 7.83 (d, 1H), 7.77-7.74 (m,1H), 7.12 (m, 1H), 7.03-6.90 (m, 4H), 6.04 (s, 1H), 3.15-3.09 (m, 6H),2.65-2.58 (m, 6H), 2.49 (t, 2H), 2.02-1.87 (m, 2H), 1.72-1.65 (m, 2H),0.98 (t, 3H)

Example 1761-phenyl-4-(3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 176)

36 mg (86%) of target compound was obtained by using a method same as inExample 1 by using 3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propanal (26mg, 0.108 mmol), 1-phenylpiperazine (0.016 mL, 0.108 mmol), DIPEA (0.028mL, 0.162 mmol) and NaBH(OAc)₃ (69 mg, 0.325 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.57-7.43 (m, 5H), 7.26-7.21 (m, 2H), 6.96(d, 2H, J=7.9 Hz), 6.85 (t, 1H, J=7.3 Hz), 6.22 (s, 1H), 3.18-3.15 (m,4H), 3.00-2.95 (m, 1H), 2.74-2.68 (m, 2H), 2.66-2.63 (m, 4H), 2.49-2.45(m, 2H), 1.85-1.79 (m, 2H), 1.29 (d, 6H, J=6.9 Hz)

Example 1771-(2-fluorophenyl)-4-(3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 177)

143 mg (99%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propanal(86 mg, 0.357 mmol), 1-(2-fluorophenyl)piperazine (65 mg, 0.362 mmol),DIPEA (0.094 mL, 0.540 mmol) and NaBH(OAc)₃ (237 mg, 1.118 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.58-7.44 (m, 5H), 7.07-6.97 (m, 4H), 6.22(s, 1H), 3.11-3.08 (m, 4H), 3.03-2.93 (m, 1H), 2.74-2.69 (m, 6H),2.54-2.40 (m, 2H), 1.89-1.78 (m, 2H), 1.29 (d, 3H, J=6.9 Hz)

Example 1781-phenyl-4-(3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 178)

100 mg (80%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propanal (80mg, 0.312 mmol), 1-phenylpiperazine (0.047 mL, 0.312 mmol), DIPEA (0.081mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.58-7.43 (m, 5H), 7.27-7.21 (m, 2H),6.98-6.95 (m, 2H), 6.88-6.83 (m, 1H), 6.24 (s, 1H), 3.62-3.45 (m, 4H),3.20-3.01 (m, 8H), 2.80-2.68 (m, 2H), 2.59 (t, 2H, J=7.5 Hz), 2.16-1.99(m, 2H), 1.74-1.59 (m, 2H), 0.94 (t, 3H, J=7.3 Hz)

Example 1791-(2-fluorophenyl)-4-(3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 179)

196.6 mg (86%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propanal (140mg, 0.546 mmol), 1-(2-fluorophenyl)piperazine (130 mL, 0.819 mmol), andNaBH(OAc)₃ (excess amount).

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.39 (m, 5H), 7.03-6.89 (m, 4H), 6.03 (s,1H), 3.06 (t, 4H), 2.70-2.61 (m, 4H), 2.54 (t, 4H), 2.38 (t, 2H),1.81-1.76 (m, 2H), 1.68-1.63 (m, 2H), 1.44-1.36 (m, 2H), 0.93 (t, 3H)

Example 1801-(2-fluorophenyl)-4-(3-(1-(3-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 180)

312 mg (84.2%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(3-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (236.75 mg, 0.814mmol), 1-(2-fluorophenyl)piperazine (192.9 mL, 1.221 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.29-7.20 (m, 3H), 7.03-6.89 (m, 6H), 5.89 (s,1H), 5.25 (s, 2H), 3.06 (t, 4H), 2.60 (t, 2H), 2.53-2.48 (m, 6H), 2.34(t, 2H), 1.76-1.71 (m, 2H), 1.65-1.58 (m, 2H), 1.42-1.35 (m, 2H), 0.92(t, 3H)

Example 1811-(2-fluorophenyl)-4-(3-(1-(4-methoxyphenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 181)

308 mg (78%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-methoxyphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (251 mg, 0.876mmol), 1-(2-fluorophenyl)piperazine (208 mL, 1.314 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.31-7.29 (m, 2H), 7.04-6.90 (m, 6H), 6.00 (s,1H), 3.82 (s, 3H), 3.07 (m, 4H), 2.64-2.57 (m, 8H), 2.38 (m, 2H),1.81-1.76 (m, 2H), 1.69-1.59 (m, 2H), 1.45-1.35 (m, 2H), 0.92 (t, 3H)

Example 1821-(2-fluorophenyl)-4-(3-(1-(4-methylphenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 182)

297 mg (70.6%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-methylphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (248 mg, 0.968mmol), 1-(2-fluorophenyl)piperazine (229 mL, 1.451 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.28-7.26 (m, 2H), 7.18 (d, 2H), 6.99-6.92 (m,2H), 6.92-6.83 (m, 2H), 6.00 (s, 1H), 3.03 (t, 4H), 2.65-2.60 (m, 4H),2.50 (t, 4H), 2.36-2.32 (m, 5H), 1.78-1.67 (m, 2H), 1.65-1.59 (m, 2H),1.43-1.44 (m, 2H), 0.91 (t, 3H)

Example 1831-(2-fluorophenyl)-4-(3-(1-(4-fluorophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 183)

218 mg (87.5%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-fluorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (155.9 mg, 0.568mmol), 1-(2-fluorophenyl)piperazine (106 mL, 0.852 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.40-7.35 (m, 2H), 7.13-7.08 (m, 2H),7.03-6.88 (m, 4H), 6.02 (s, 1H), 3.06 (t, 4H), 2.64-2.59 (m, 4H), 2.54(t, 4H), 2.37 (t, 2H), 1.80-1.67 (m, 2H), 1.66-1.59 (m, 2H), 1.43-1.36(m, 2H), 0.92 (t, 3H)

Example 1841-(2-fluorophenyl)-4-(3-(1-(4-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 184)

98.4 mg (78.5%) of target compound was obtained by using a method sameas in Example 1 by using3-(1-(4-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (80.1 mg, 0.275mmol), 1-(2-fluorophenyl)piperazine (65 mL, 0.413 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.38-7.34 (m, 4H), 7.02-6.87 (m, 4H), 6.03 (s,1H), 3.05 (t, 4H), 2.67-2.59 (m, 4H), 2.54 (t, 4H), 2.37 (t, 2H),1.83-1.75 (m, 2H), 1.69-1.59 (m, 2H), 1.43-1.35 (m, 2H), 0.92 (t, 3H)

Example 1851-(2-fluorophenyl)-4-(3-(1-(4-trifluoromethylphenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 185)

258.6 mg (84.7%) of target compound was obtained by using a method sameas in Example 1 by using3-(1-(4-trifluoromethylphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (202.6mg, 0.625 mmol), 1-(2-fluorophenyl)piperazine (148 mL, 0.937 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, 2H), 7.58 (d, 2H), 7.04-7.00 (m, 2H),6.96-6.88 (m, 2H), 6.08 (s, 1H), 3.06 (t, 4H), 2.72 (t, 2H), 2.64 (t,2H), 2.56 (t, 4H), 2.40 (t, 2H), 1.85-1.80 (m, 2H), 1.68-1.63 (m, 2H),1.44-1.37 (m, 2H), 0.93 (t, 3H)

Example 1861-(2-fluorophenyl)-4-(3-(1-(4-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 186)

260 mg (90.0%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(4-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (187 mg, 0.625mmol), 1-(2-fluorophenyl)piperazine (148 mL, 0.937 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.30-8.27 (m, 2H), 7.67-7.64 (m, 2H),7.02-6.88 (m, 4H), 6.11 (s, 1H), 3.05 (t, 4H), 2.77 (t, 2H), 2.64 (t,2H), 2.56 (t, 4H), 2.41 (t, 2H), 1.87-1.82 (m, 2H), 1.67-1.58 (m, 2H),1.42-1.35 (m, 2H), 0.92 (t, 3H)

Example 1871-(2-fluorophenyl)-4-(3-(1-benzyl-3-butyl-4H-pyrazol-5-yl)propyl)piperazine(Compound 187)

180 mg (84.2%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-benzyl-3-butyl-1H-pyrazol-5-yl)propanal (133mg, 0.492 mmol), 1-(2-fluorophenyl)piperazine (155 mL, 0.984 mmol), andNaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.32 (m, 5H), 7.01-6.89 (m, 4H), 6.03 (s,1H), 3.06 (t, 4H), 2.70-2.61 (m, 4H), 2.54 (t, 4H), 2.38 (t, 2H),1.81-1.76 (m, 2H), 1.68-1.63 (m, 2H), 1.44-1.36 (m, 2H), 0.93 (t, 3H)

Example 1881-(2-fluorophenyl)-4-(3-(1-(3-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 188)

218 mg (66.2%) of target compound was obtained by using a method same asin Example 1 by using3-(1-(3-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (213 mg, 0.707mmol), 1-(2-fluorophenyl)piperazine (167 mL, 1.060 mmol), and NaBH(OAc)₃(198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H), 8.14 (d, 1H), 7.79 (d, 1H), 7.57(t, 1H), 7.01-6.82 (m, 4H), 6.08 (s, 1H), 3.02 (m, 4H), 2.71 (t, 2H),2.63-2.56 (m, 6H), 2.41 (t, 2H), 1.88-1.81 (m, 2H), 1.65-1.57 (m, 2H),1.41-1.33 (m, 2H), 0.90 (t, 3H)

Example 1891-(2-fluorophenyl)-4-(3-(1-(2′-pyridyl)-3-butyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 189)

90 mg (78.5%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-(2′-pyridyl)-3-butyl-1H-pyrazol-5-yl)propanal(70 mg, 0.272 mmol), 1-(2-fluorophenyl)piperazine (65 mL, 0.408 mmol),and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.38-8.36 (m, 1H), 7.83 (d, 1H), 7.75-7.72 (m,1H), 7.10-7.02 (m, 1H), 7.00-6.89 (m, 4H), 6.04 (s, 1H), 3.15-3.07 (m,6H), 2.66-2.61 (m, 6H), 2.45 (t, 2H), 1.91-1.86 (m, 2H), 1.67-1.62 (m,2H), 1.43-1.39 (m, 2H), 0.93 (t, 3H)

Example 1901-phenyl-4-(3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 190)

120 mg (95%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propanal(80 mg, 0.312 mmol), 1-phenylpiperazine (0.047 mL, 0.312 mmol), DIPEA(0.081 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.57-7.43 (m, 5H), 7.26-7.21 (m, 2H), 6.96(d, 2H, J=7.9 Hz), 6.85 (t, 1H, J=7.3 Hz), 6.22 (s, 1H), 3.18-3.15 (m,4H), 3.00-2.95 (m, 1H), 2.74-2.68 (m, 4H), 2.66-2.63 (m, 4H), 2.49-2.45(m, 2H), 1.85-1.79 (m, 2H), 1.29 (d, 6H, J=6.9 Hz)

Example 1911-(2-fluorophenyl)-4-(3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propyl)piperazine(Compound 191)

121 mg (92%) of target compound was obtained by using a method same asin Example 1 by using 3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propanal(80 mg, 0.312 mmol), 1-(2-fluorophenyl)piperazine (56 mg, 0.312 mmol),DIPEA (0.082 mL, 0.468 mmol) and NaBH(OAc)₃ (198 mg, 0.936 mmol).

¹H NMR (300 MHz, MeOH-d₄) δ 7.58-7.44 (m, 5H), 7.07-6.97 (m, 4H), 6.22(s, 1H), 3.11-3.08 (m, 4H), 3.03-2.93 (m, 1H), 2.74-2.69 (m, 8H),2.54-2.40 (m, 2H), 1.89-1.78 (m, 2H), 1.29 (d, 3H, J=6.9 Hz)

REFERENCE EXAMPLES

The following reference examples are embodiments of methods forpreparing the compound represented by the above formula 2 according tothe reaction scheme II, however, they should not be construed aslimiting the scope of the present invention.

Reference Example 1 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione(Formula 5)

To 60 mL of benzene was added NaOMe (5.4 g, 99.612 mmol) under nitrogenatmosphere and stirred. The above mixture was added then with 30 mL of4-chloroacetophenone (5.9 mL, 45.278 mmol) after mixing it with 30 mL ofbenzene and stirred for 30 min at 40° C. Then, γ-butyrolactone (7.0 mL,90.556 mmol), after mixing it with 30 mL of benzene, was slowly addedthereto and stirred for 16 hrs at 40° C. The progress and completion ofthe reaction were confirmed by means of TLC. Upon completion of thereaction, the reaction mixture was cooled down to room temperature andthe solvent was removed from the reaction mixture under reducedpressure. The reaction mixture was diluted with EtOAc, and added withwater. The aqueous layer was extracted with EtOAc and the organic layerwas dried with anhydrous MgSO₄ and filtered. The resulting filtrate wasconcentrated under reduced pressure and the resulting concentrate waspassed through column chromatography (EtOAc:Hexane=1:1, v/v) to obtain5.9 g (54%) of target compound.

¹H NMR (400 MHz, CDCl₃) δ 7.87-7.74 (m, 2H), 7.42-7.31 (m, 2H), 6.47 (s,1H), 4.31 (t, 2H, J=7.0 Hz), 3.31-3.23 (m, 2H), 2.21-2.10 (m, 2H)

Reference Example 23-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propane-1-ol (Formula6a)

1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione (2.0 g, 8.310 mmol) wasdissolved in 15 mL of methanol. t-BuNHNH₂.HCl (2.1 g, 16.620 mmol) wasdissolved in 15 mL of methanol and then added with triethylamine (TEA;2.3 mL, 16.620 mmol). After they were all dissolved, the mixture wasadded into a solution of 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione,and then stirred for 14 hours at 40° C. The reaction progress andcompletion were confirmed by TLC. Upon completion of the reaction, whilethe temperature was kept at room temperature, the solvent was removedunder reduced pressure. The reaction residue was diluted with EtOAc, andadded with water. The aqueous layer was extracted with EtOAc and theorganic layer was dried with anhydrous MgSO₄ and filtered andconcentrated under reduced pressure. The concentrate was separated bycolumn chromatography (EtOAc:Hexane=2:3, v/v) to obtain 1.57 g (64%) oftarget compound.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, 2H, J=8.1 Hz), 7.26 (d, 2H, J=8.3Hz), 5.93 (s, 1H), 3.76 (t, 2H, J=5.7 Hz), 2.78 (t, 2H, J=6.7 Hz),1.97-1.90 (m, 2H), 1.43 (s, 9H)

Reference Example 3 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propan-1-ol(formula 6a) and 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propan-1-ol(Formula 6b)

1-hydroxynonane-4,6-dione (3.5 g, 20.3 mmol) was dissolved in 10 mL ofmethanol. t-BuNHNH₂.HCl (7.6 g, 60.968 mmol) was dissolved in 30 mL ofmethanol and then added with TEA (8.5 mL, 61.0 mmol). After they wereall dissolved, the mixture was added into a solution of1-hydroxynonane-4,6-dione and then stirred for 12 hrs at 40° C. Thereaction progress and completion were confirmed by TLC. Upon completionof the reaction, while the temperature was kept at room temperature, thesolvent was removed under reduced pressure. The reaction residue wasdiluted with EtOAc, and added with water. The aqueous layer wasextracted with EtOAc and the organic layer was dried with anhydrousMgSO₄ and filtered and concentrated under reduced pressure. Theconcentrate was separated by column chromatography (Ether:Hexane=1:1) toobtain target 1.686 g (37%) of compound (formula 6a) and 1.540 g (34%)of target compound (formula 6b).

3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propan-1-ol (formula 6a)

¹H NMR (400 MHz, MeOH-d₄) δ 5.94 (s, 1H), 3.58 (t, 2H, J=6.5 Hz), 2.78(t, 2H, J=7.7 Hz), 2.60 (t, 2H, J=7.6 Hz), 1.88-1.78 (m, 2H), 1.78-1.64(m, 2H), 1.60 (s, 9H), 1.04 (t, 3H, J=7.5 Hz).

3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propan-1-ol (formula 6b)

¹H NMR (400 MHz, CDCl₃) δ 5.88 (s, 1H), 3.74 (t, 2H, J=6.2 Hz), 2.87 (t,2H, J=7.8 Hz), 2.53 (t, 2H, J=7.8 Hz), 1.98-1.86 (m, 2H), 1.69-1.53 (m,2H), 1.61 (s, 9H), 0.96 (t, 3H, J=7.3 Hz).

Reference Example 43-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (Formula 2)

3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propan-1-ol (200 mg,0.774 mmol), PCC (334 mg, 1.548 mmol), SiO₂ (334 mg) was added with 5 mLof CH₂Cl₂ under nitrogen atmosphere and stirred for 5 hrs at roomtemperature. The progress and completion of the reaction were confirmedby means of TLC. Upon completion of the reaction, the reaction mixturewas cooled down to room temperature and the solvent was removed from thereaction mixture under reduced pressure. The reaction mixture wasdiluted with EtOAc, and added with water. The aqueous layer wasextracted with EtOAc and the organic layer was dried with anhydrousMgSO₄ and filtered. The resulting filtrate was concentrated underreduced pressure and the resulting concentrate was passed through columnchromatography (Ether:Hexane=2:3, v/v) to obtain 149 mg (75%) of targetcompound.

¹H NMR (400 MHz, CDCl₃) δ 9.88 (t, 1H, J=1.6 Hz), 7.38-7.33 (m, 2H),7.27-7.23 (m, 2H) 5.91 (s, 1H), 2.98 (t, 2H, J=7.2 Hz), 2.85-2.78 (m,2H), 1.41 (s, 9H)

EXPERIMENTAL EXAMPLES Experimental Example 1 Measurement of Affinity forDopamine D₄ Receptor

Compounds represented by the above formula 1 were measured of theiraffinities for dopamine D₄ receptor by the method described below.

The affinities of the compounds for dopamine D₄ receptor were measuredby using human recombinant dopamine D_(4.2) receptor (PerkinElmer Lifeand Analytical Sciences, USA) expressed in CHO-K1 cells, and[³H]YM-09151-2 (PerkinElmer) was used as a radioactive ligand.

50 mM Tris-HCl (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 5 mM MgCl₂ and1 mM EDTA was used as a buffer solution for the analysis of receptorbinding. [³H] YM-09151-2 binding reactions were performed in a 96-wellplate format.

For drug screening, a reaction mixture with a final volume of 0.25 mLwas prepared by mixing a compound of the present invention, D₄ receptormembrane (43 μg/well), [³H] YM-09151-2 (0.1 nM), 50 mM Tris-HCl (pH 7.4)and the like. The reaction mixture was incubated for 120 min at 25° C.,and then promptly passed through Wallac GF/C glass fiber filter (Wallac,Finland), which was already wetted in 0.5% PEI, by using Inotechharvester (Inotech) to terminate the reaction, and then washed with cold50 mM Tris-HCl buffer solution. The filter was then covered withMeltiLex, sealed in a sample bag, and then dried in an oven. Theradioactivity retained in the filter was finally counted using MicroBetaPlus, Wallac.

The affinity (IC50) of a compound for the receptor was calculated vianonlinear regression analysis of sigmoidal dose-response equation withthe data obtained from three independent experiments (GraphPad PrismProgram, San Diego, USA), which are carried out using 7-8 differentconcentrations of the compound in duplicate. Nonspecific binding wasmeasured in the presence of 10 μM clozapine.

As shown in the Table 1, compounds 155, 156, 159, 160, 163 and 177showed very high affinities for dopamine D₄ receptor (IC₅₀<10 nM).

TABLE 1 D₄ receptor affinity Tested Compound (IC₅₀, nM) Compound 155 5.9Compound 156 3.5 Compound 159 1.3 Compound 160 2.9 Compound 163 7.7Compound 177 8.0

Experimental Example 2 Evaluation of Selectivity on Dopamine D₄ Receptor

In order to evaluate the selectivity of the compounds which showedsuperior affinities for dopamine D₄ receptor in Experimental Example 1above, their affinities for the other dopamine receptor isotypes andserotonin receptors were measured, respectively.

2-1: Measurement of Affinities for Dopamine Receptor Isotypes (D₂ & D₃)

Human recombinant dopamine D₂ and D₃ receptors, which were expressed inCHO cell lines, respectively, were purchased from PerkinElmer andEuroscreen, respectively. The affinities for D₂ and D₃ dopaminereceptors were determined by adding receptor membrane (3 and 1 ug/well,respectively), radioactive isotope [³H] spiperone (0.5 and 0.8 nM,respectively) and a test compound to a buffer solution, and subsequentlyincubating for 60 min at 27° C., and finally measuring the radioactivityusing Inotech Harvester after filtration same as in Experimental Example1 above.

50 mM Tris-HCl (pH 7.4) containing 10 MgCl₂ and 1 mM EDTA was used as abuffer solution for the measurement of affinity for dopamine D₂receptor. 50 mM Tris-HCl (pH 7.4) containing 5 mM MgCl₂, 5 mM EDTA, 5 mMKCl, 1.5 mM CaCl₂ and 120 mM NaCl was used as a buffer solution for themeasurement of affinity for dopamine D₃ receptor. For measurement ofnon-specific binding, 10 μM haloperidol (haloperidol) was used.

2-2: Measurement of Affinity for Serotonin 5-HT Receptor Family

The measurement of affinity for serotonin 5-HT receptor family wasperformed according to the experimental conditions as specified in Table2 below using the method same as in Experimental Example 1 above.

The detailed conditions of the analysis are shown in Table 2 below.

TABLE 2 Conditions for analysis of serotonin receptor binding experimentReceptor 5-HT_(1A) 5-HT_(2A) 5-HT_(2c) 5-HT₆ 5-HT₇ Receptor Stable CHOor HEK-293 cell lines expressing human or rat membrane recombinantreceptors source Buffer 50 mM Tris-HCl 50 mM Tris- 50 mM Tris-HCl 50 mMTris-HCl solution (pH 7.4), 10 mM HCl (pH 7.4) (pH 7.7), 0.1% (pH 7.4),10 mM MgSO₄, 0.5 mM ascorbic acid, MgCl₂, 0.5 mM EDTA, 0.1% 10 μMpargyline EDTA ascorbic acid Final Volume 250 μL Radioactive[³H]8-OH-DPAT, [³H]ketanserin [³H]Mesulergine [³H] [³H] ligand 0.5 nM 1nM 1 nM LSD LSD 1.8 nM 3 nM Non-specific methiothepin mianserinmethiothepin binding 0.5 μM 1 μM 10 μM Culture 60 min at 27° C. 15 minat 37° C. 30 min at 37° C. 60 min 90 min at 37° C. at 27° C. FiltrationGF/C GF/C GF/C GF/C 0.5% PEI 0.05% Brij 1% BSA 0.5% PEI

The results of affinity measurements of compounds of the presentinvention for dopamine and serotonin receptor isotypes are shown inTable 3.

TABLE 3 Receptor affinity (IC₅₀, nM) Tested 5- 5- Compounds D₂ D₃5-HT_(1A) HT_(2A) HT_(2C) 5-HT₆ 5-HT₇ Compound 155 5264 461 109 35671 >10000 259 Compound 156 696 87 126 152 1396 >10000 313 Compound 1592046 131 413 8 154 2504 195 Compound 160 3794 229 50 65 141 2014 84Compound 163 1056 420 494 45 558 617 651 Compound 177 227 687 37 27 5059214 252

As shown in Table 3 above, compounds 155, 156, 159, 160, 163 and 177 ofthe present invention showed poor affinities for dopamine receptorisotypes (D2 & D3) and serotonin receptors. In particular, they showedextremely poor affinity for D2 receptors, which are very closelyassociated with adverse reactions induced by a therapeutic agent forschizophrenia.

Further, the above compounds also showed relatively poor affinity forserotonin receptors (5-HT_(1A)-5-HT₇) except for 5-HT_(2A) receptor.Therefore, the compounds of 155-177 of the present invention wereconfirmed to have superior selectivity for D₄ receptors.

Experimental Example 3 Measurement of Influences on Apomorphine-InducedBehavior in Mice

To evaluate the effect of the compounds of the present invention againstschizophrenia, which were shown to have excellent affinity for receptorsin the above Table 1, the inhibitory effects of the compounds onapomorphine-induced psychiatric behavior, cage climbing, in mice weremeasured.

When mice were treated with apomorphine (1 mg/kg, sc), a potent dopaminereceptor agonist, and were put into cylindrical cages (diameter, 12cm/height, 14 cm) with the floor and wall consisting of metal bars andcovered with a lid, they begin to perform repeatedly a psychoticbehavior of ‘cage climbing’. Their climbing behaviors were monitoredevery 10 min for 30 min and scored by 4-point rating scale (0˜3 points)depending on the extent of the behavior (Costentin, J. et al., Nature1975, 257, 405-7; Protais, P. et al., Psychopharmacology 1976, 50, 1-6).

The compounds were injected intraperitoneally into mice 30 min prior toapomorphine administration. The inhibitory effects of the compoundsagainst control group were measured and each ED₅₀ was calculatedtherefrom.

The compounds 155, 156, 157, 159, 160 and 177 of the present inventionsignificantly inhibited the psychotic behavior induced by apomorphine(ED₅₀: 8.8-14.5 mg/kg, ip). In fact, their effects were a little bitless than that of clozapine (4 mg/kg, ip), the most effective D₄receptor antagonist for schizophrenia at present, thus proving that theyhave an excellent effect on treating psychotic diseases. ED₅₀ of eachcompound is shown in Table 4 below.

TABLE 4 Effects of Compounds of the present invention on psychoticdiseases Inhibitory effects on apomorphine-induced climbing TestedCompounds behavior ED₅₀ (mg/kg, ip) Compound 155 10.7 Compound 156 9.6Compound 157 14.5 Compound 159 9.1 Compound 160 10.6 Compound 177 8.8clozapine (reference 4.0 compound)

Experimental Example 4 Effects on Rotarod Deficit in Mice

Rotarod test was performed to evaluate the effect of the compounds ofthe present invention on extrapyramidal side effects in mice as follows(Dunham, N. W. et al., J. Am. Pharm. Assoc. 1957, 46, 208-209). Eachmouse was administered with a test drug, and then placed on a 1 inchdiameter knurled plastic rod rotating at 6 rpm (Ugo-Basile, Milano,Italy), and the rotarod deficit (%) was obtained by counting the numberof mice fallen from the rotating rod within 1 min at 30, 60, 90, and 120min after the administration of the drug. The median neurotoxic dose(TD₅₀) was determined as the dose at which 50% of the mice showedrotarod deficit.

TABLE 5 Rotarod deficit Tested Compound TD₅₀ (mg/kg, ip) Compound 15528.5 Compound 156 26.0 Compound 157 50.1 Compound 159 35.3 Compound 16024.6 Compound 177 19.4 clozapine 3.9

As shown in the above Table 5, the compounds 155, 156, 157, 159, 160 and177 of the present invention showed about 20-50 mg/kg (ip) of rotaroddeficit TD₅₀. This is about 2.2-5 times of ED₅₀ for antipsychoticefficacy, and thus the above compounds were proved to be relatively safeas a drug working on central nervous system with low extrapyramidal sideeffects (EPS). In case of clozapine, a reference drug, there wereobserved adverse effects at dosage showing efficacies as shown in theabove table (ED₅₀ and TD₅₀ are almost same).

Therefore, the compounds of the present invention are shown to be a safedrug having less adverse effects than those of clozapine, a referencedrug.

MANUFACTURING EXAMPLES

The compounds of the present invention represented by the above formula1 can be formulated in various forms. The followings are embodiments offormulation methods comprising the above compounds as active ingredient.However, they should not be construed as limiting the scope of thepresent invention.

Formulation 1 Preparation of Tablets

100 mg of a compound of the present invention or its pharmaceuticallyacceptable salt, 100 mg of corn starch, 100 mg of lactose and 2 mg ofstearate magnesium were mixed and formulated into tablets according to aconventional tableting method.

Formulation 2 Preparation of Capsules

100 mg of a compound of the present invention or its pharmaceuticallyacceptable salt, 100 mg of corn starch, 100 mg of lactose and 2 mg ofstearate magnesium were mixed and formulated into capsules according toa conventional capsulation method by filling the ingredients into agelatin capsule.

Formulation 3 Preparation of Powder

2 g of a compound of the present invention or its pharmaceuticallyacceptable salt and 1 g of corn starch were mixed and filled into asealing to be formulated into powder.

INDUSTRIAL APPLICABILITY

The piperazinyl-propyl-pyrazole derivatives of the present inventionrepresented by the above formula 1 are shown to have excellent bindingaffinities for dopamine D₄ receptor. They are also shown to effectivelyinhibit psychotic behavior (cage climbing) in mice induced byapomorphine. Further, they have shown relatively low level of adverseeffects in mice rotarod test, thus being expected to be very useful as atherapeutic agent for the prevention and treatment of schizophrenia,attention deficit hyperactivity disorder, depression, stress diseases,panic disorder, phobia, obsessive-compulsive disorder, posttraumaticstress disorder, cognitive disorder, Alzheimer's disease, Parkinson'sdisease, anxiety, paraphrenia, mania, seizure disorder, personalitydisorder, migraine, drug addiction, alcohol addiction, obesity, eatingdisorder, sleeping disorder and the like.

1. A piperazinyl-propyl-pyrazole derivative or its pharmaceuticallyacceptable salt represented by the following formula 1:

wherein R1 is a C1-C10 alkyl group, or a substituted or unsubstitutedaryl or heteroaryl group; one of R2 and R3 is a C1-C10 alkyl group,benzyl group, or substituted or unsubstituted aryl or heteroaryl group,such that only one of R2 and R3 is present which would result in apyrazole ring; R4, R5, R6 and R7, being same or different with oneanother, are independently a hydrogen atom or a C1-C10 alkyl group; R8,R9, R10, R11 and R12, being same or different with one another, areindependently a hydrogen atom, a halogen atom, a C1-C10 alkyl group, aC1-C10 alkoxy group, a bis(substituted or unsubstituted aryl)alkylenegroup, a benzyl group, a nitro group, a hydroxy group, a cyano group, anamino group, a mono or dialkylamino group, an alkylcarbonylamino group,an aminosulfonyl group, a mono or dialkylaminosulfonyl group, analkylcarbonyl group, or an alkyloxycarbonyl group; the dotted linerepresents a single bond or a double bond which depends on the presenceof either R2 or R3 to maintain the aromaticity of a pyrazole ring; saidaryl group represents a phenyl group, said heteroaryl group represents athiophenyl group or a pyridyl group, and said substituted aryl orheteroaryl group represents an aryl or a heteroaryl group with from 1 to3 substituents selected from the group consisting of a halogen atom, anitro group, a C1-C10 alkyl group, a C1-C10 alkoxy group, a C1-C10haloalkyl group, and a C1-C10 haloalkoxy.
 2. Thepiperazinyl-propyl-pyrazole derivative or its pharmaceuticallyacceptable salt of claim 1, wherein said R1 is a C1-C10 alkyl group, asubstituted or unsubstituted phenyl group, or a substituted orunsubstituted thiophenyl group; one of R2 and R3 is a C1-C10 alkylgroup, benzyl group, a substituted or unsubstituted phenyl group, or asubstituted or unsubstituted pyridyl group, such that only one of R2 andR3 is present which would result in a pyrazole ring; R4, R5, R6 and R7,being same or different with one another, are independently a hydrogenatom or a C1-C10 alkyl group; R8, R9, R10, R11 and R12, being same ordifferent with one another, are independently a hydrogen atom, a halogenatom, a C1-C10 alkyl group, a C1-C10 alkoxy group, bis(substituted orunsubstituted phenyl)alkylene group, or a benzyl group; the dotted linerepresents a single bond or a double bond which depends on thesubstitution of R2 and R3 but maintains the aromaticity of a pyrazolering; said substituted phenyl group, thiophenyl group or pyridyl groupare independently a phenyl group, a thiophenyl group or a pyridyl groupwith from 1 to 3 substituents selected from the group consisting of ahalogen atom, a nitro group, a C1-C10 alkyl group, a C1-C10 alkoxygroup, a C1-C10 haloalkyl group, and a C1-C10 haloalkoxy group.
 3. Thepiperazinyl-propyl-pyrazole derivative or its pharmaceuticallyacceptable salt of claim 1, wherein said R1 is phenyl, 4-methylphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-thiophenyl, methyl,ethyl, propyl, isopropyl, butyl, or isobutyl; one of R2 and R3 ist-butyl, benzyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chlorophenyl,4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl,4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, or 2-pyridyl, suchthat only one of R2 and R3 is present which would result in a pyrazolering; R4, R5, R6 and R7, being same or different with one another, areindependently a hydrogen atom or a methyl group; R8, R9, R10, R11 andR12, being same or different with one another, are independently ahydrogen atom, a chloro, fluoro, methyl, methoxy, orbis(4-fluorophenyl)methylene.
 4. The piperazinyl-propyl-pyrazolederivative or its pharmaceutically acceptable salt of claim 1, whereinsaid pharmaceutically acceptable salt is produced by reacting saidderivative represented by the above formula 1 with an inorganic acid, anorganic acid, an amino acid, sulfonic acid, an alkali metal or ammoniumion.
 5. A method of preparing a piperazinyl-propyl-pyrazole derivativerepresented by the following formula 1 by performing reductive aminationbetween a pyrazole aldehyde derivative represented by the followingformula 2 and a piperazine derivative represented by the followingformula 3:

wherein, in the above reaction scheme I, R1, R2, R3, R4, R5, R6, R7, R8,R9, R10, R11 and R12 are same as defined in claim
 1. 6. The method ofclaim 5, wherein said reductive amination is performed in the presenceof a molecular sieve, a reducing agent and a base.
 7. A pharmaceuticalcomposition for the treatment of central nervous system disorderscomprising a compound selected from claim
 1. 8. A pharmaceuticalcomposition for the treatment of central nervous system disorderscomprising a compound selected from claim
 2. 9. A pharmaceuticalcomposition for the treatment of central nervous system disorderscomprising a compound selected from claim
 3. 10. A pharmaceuticalcomposition for the treatment of central nervous system disorderscomprising a compound selected from claim 4.